Carbamoyl Compounds as DGAT1 Inhibitors 190

ABSTRACT

DGAT-1 inhibitor compounds of formula (1), pharmaceutically-acceptable salts and pro-drugs thereof are described, together with pharmaceutical compositions, processes for making them and their use in treating, for example, obesity 
     
       
         
         
             
             
         
       
         
         wherein, for example, 
         Ring A is optionally substituted 2,6-pyrazindiyl; 
         X is ═0; 
         Ring B is optionally substituted 1,4-phenylene; 
         Y 1  is a direct bond or —O—; 
         Y 2  is —(CH 2 ) r — wherein r is 2 or 3; 
         n is 0 or n is 1 when Y 1  is a direct bond between Ring B and Ring C and when Ring B is 1,4-phenylene and Ring C is (4-6C)cycloalkane; 
         Ring C is optionally substituted (4-6C)cycloalkane, (7-10C)bicycloalkane, (8-12C)tricycloalkane, phenylene or pryidindiyl; 
         L is a direct bond or —O—; 
         p is 0, 1 or 2 and when p is 1 or 2 R A1  and R A2  are each independently hydrogen or (1-4C)alkyl; 
         Z is carboxy or a mimic or bioisostere thereof.

This application claims the benefit under 35 U.S.C. §119(e) ofApplication No. 61/015,397 US filed on 20 Dec. 2007.

The present invention relates to compounds which inhibit acetylCoA(acetyl coenzyme A): diacylglycerol acyltransferase (DGAT1) activity,processes for their preparation, pharmaceutical compositions containingthem as the active ingredient, methods for the treatment of diseasestates associated with DGAT1 activity, to their use as medicaments andto their use in the manufacture of medicaments for use in the inhibitionof DGAT1 in warm-blooded animals such as humans. In particular thisinvention relates to compounds useful for the treatment of type IIdiabetes, insulin resistance, impaired glucose tolerance and obesity inwarm-blooded animals such as humans, more particularly to the use ofthese compounds in the manufacture of medicaments for use in thetreatment of type II diabetes, insulin resistance, impaired glucosetolerance and obesity in warm-blooded animals such as humans.

Acyl CoA:diacylglycerol acyltransferase (DGAT) is found in themicrosomal fraction of cells. It catalyzes the final reaction in theglycerol phosphate pathway, considered to be the main pathway oftriglyceride synthesis in cells by facilitating the joining of adiacylglycerol with a fatty acyl CoA, resulting in the formation oftriglyceride. Although it is unclear whether DGAT is rate-limiting fortriglyceride synthesis, it catalyzes the only step in the pathway thatis committed to producing this type of molecule [Lehner & Kuksis (1996)Biosynthesis of triacylglycerols. Prog. Lipid Res. 35: 169-201].

Two DGAT genes have been cloned and characterised. Both of the encodedproteins catalyse the same reaction although they share no sequencehomology. The DGAT1 gene was identified from sequence database searchesbecause of its similarity to acyl CoA:cholesterol acyltransferase (ACAT)genes. [Cases et al (1998) Identification of a gene encoding an acylCoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerolsynthesis. Proc. Natl. Acad. Sci. USA 95: 13018-13023]. DGAT1 activityhas been found in many mammalian tissues, including adipocytes.

Because of the previous lack of molecular probes, little is known aboutthe regulation of DGAT1. DGAT1 is known to be significantly up-regulatedduring adipocyte differentiation.

Studies in gene knockout mice has indicated that modulators of theactivity of DGAT1 would be of value in the treatment of type II diabetesand obesity. DGAT1 knockout (DgatI^(−/−)) mice, are viable and capableof synthesizing triglycerides, as evidenced by normal fasting serumtriglyceride levels and normal adipose tissue composition. Dgat1^(−/−)mice have less adipose tissue than wild-type mice at baseline and areresistant to diet-induced obesity. Metabolic rate is ˜20% higher inDgatI^(−/−) mice than in wild-type mice on both regular and high-fatdiets [Smith et al (2000) Obesity resistance and multiple mechanisms oftriglyceride synthesis in mice lacking DGAT. Nature Genetics 25: 87-90].Increased physical activity in Dgat1^(−/−) mice partially accounts fortheir increased energy expenditure. The Dgat1^(−/−) mice also exhibitincreased insulin sensitivity and a 20% increase in glucose disposalrate. Leptin levels are 50% decreased in the Dgat1^(−/−) mice in linewith the 50% decrease in fat mass.

When Dgat1^(−/−) mice are crossed with ob/ob mice, these mice exhibitthe ob/ob phenotype [Chen et al (2002) Increased insulin and leptinsensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase J.Clin. Invest. 109:1049-1055] indicating that the Dgat1^(−/−) phenotyperequires an intact leptin pathway. When Dgat1^(−/−) mice are crossedwith Agouti mice a decrease in body weight is seen with normal glucoselevels and 70% reduced insulin levels compared to wild type, agouti orob/ob/Dgat1^(−/−) mice.

Transplantation of adipose tissue from Dgat1^(−/−) mice to wild typemice confers resistance to diet-induced obesity and improved glucosemetabolism in these mice [Chen et al (2003) Obesity resistance andenhanced glucose metabolism in mice transplanted with white adiposetissue lacking acyl CoA:diacylglycerol acyltransferase J. Clin. Invest.111: 1715-1722].

International Application WO 2006/064189 describes certain oxadiazolecompounds which inhibit DGAT-1. However, there remains a need forfurther DGAT-1 inhibitors possessing desirable properties, such as, forexample, pharmaco-kinetic/dynamic and/or physico-chemical and/ortoxicological profiles.

Accordingly, the present invention provides a compound of formula (I),or a pharmaceutically-acceptable salt, or pro-drug thereof,

whereinRing A is 2,6-pyrazindiyl, 3,5-pyridindiyl or 2,6-pyridindiyl, eachoptionally substituted on an available carbon atom by one or twosubstituents independently selected from linear (1-3C)alkyl,(2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino andcyano;

X is ═O or ═S;

Ring B is 1,4-phenylene or Ring B is a di-linked (excluding links viathe same or adjacent atoms) ring selected from pyridindiyl, furandiyl,thiophendiyl, pyrroldiyl, oxazoldiyl, thiazoldiyl, imidazoldiyl,isoxazoldiyl, isothiazoldiyl and pyrazoldiyl; each optionallysubstituted on an available carbon atom by one or two substituentsindependently selected from halo, amino, cyano, (1-4C)alkyl,(2-3C)alkenyl, (2-3C)alkynyl, (1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl;Y₁ is a direct bond between Ring B and Ring C or Y₁ is —O—, —S— or —NRa—wherein Ra is hydrogen or (1-4C)alkyl;Y₂ is —(CH₂)_(r)— wherein r is 2 or 3, and Y₂ is linked at the samecarbon atom as Y₁ in Ring C and Y₂ is linked at an adjacent carbon atomto Y₁ in Ring B;n is 0 or n is 1 when Y₁ is a direct bond between Ring B and Ring C andwhen Ring B is 1,4-phenylene and Ring C is (4-6C)cycloalkane, so that a5- or 6-membered spino-ring system is formed and Ring C is tri-linked;Ring C is a di-linked (excluding links via the same or adjacent atoms)ring or ring system chosen from (4-6C)cycloalkane, (7-10C)bicycloalkaneand (8-12C)tricycloalkane each optionally substituted on an availablecarbon atom, including the ring carbon atom bearing the Z-containinggroup, by one substituent selected from hydroxy, (1-4C)alkyl,(1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl;or Ring C is a di-linked (excluding links via the same or adjacentatoms) ring selected from phenylene, pryidindiyl, piperidinediylN-linked to Y₁, piperazinediyl, furandiyl, thiophendiyl, pyrroldiyl,oxazoldiyl, thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl,pyrazoldiyl and azabicyclo[3.1.0]hexanediyl;each optionally substituted on an available carbon atom by up to foursubstituents independently selected from fluoro, chloro, bromo, cyano,(1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl;L is a direct bond to Ring C, —O—, —S— or —NH—;p is 0 (when L is a direct bond), 1 or 2 and when p is 1 or 2 R^(A1) andR^(A2) are each independently hydrogen or (1-4C)alkyl or R^(A1) andR^(A2) are linked together to form a (3-6C)spiroalkyl ring;Z is carboxy or a mimic or bioisostere thereof, hydroxy or —CONRbRcwherein Rb and Rc are independently selected from hydrogen and(1-4C)alkyl, which (1-4C)alkyl group may be optionally substituted bycarboxy or a mimic or bioisostere thereof;and wherein any carbon atom in a linear (1-3C)alkyl, (1-2C)alkoxy,(1-4C)alkyl or (1-4C)alkoxy containing group defined above may beoptionally substituted by up to 3 fluoro atoms; with the proviso thatthe compound (4-(4-(6-Carbamoyl-pyridin-2-yl)phenyl)cyclohexyl)aceticacid is excluded.

In one embodiment there is provided a compound of formula (I), or apharmaceutically-acceptable salt, or pro-drug thereof,

whereinRing A is 2,6-pyrazindiyl, 3,5-pyridindiyl or 2,6-pyridindiyl, eachoptionally substituted on an available carbon atom by one or twosubstituents independently selected from linear (1-3C)alkyl,(2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino andcyano;

X is ═O or ═S;

Ring B is 1,4-phenylene or Ring B is a di-linked (excluding links viathe same or adjacent atoms) ring selected from pyridindiyl, furandiyl,thiophendiyl, pyrroldiyl, oxazoldiyl, thiazoldiyl, imidazoldiyl,isoxazoldiyl, isothiazoldiyl and pyrazoldiyl; each optionallysubstituted on an available carbon atom by one or two substituentsindependently selected from halo, amino, cyano, (1-4C)alkyl,(2-3C)alkenyl, (2-3C)alkynyl, (1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl;Y₁ is a direct bond between Ring B and Ring C or Y₁ is —O—, —S— or —NRa—wherein Ra is hydrogen or (1-4C)alkyl;Y₂ is —(CH₂)_(r)— wherein r is 2 or 3, and Y₂ is linked at the samecarbon atom as Y₁ in RingC and Y₂ is linked at an adjacent carbon atom to Y₁ in Ring B;n is 0 or n is 1 when Y₁ is a direct bond between Ring B and Ring C andwhen Ring B is 1,4-phenylene and Ring C is (4-6C)cycloalkane, so that a5- or 6-membered spiro-ring system is formed;Ring C is a di-linked (excluding links via the same or adjacent atoms)ring or ring system chosen from (4-6C)cycloalkane, (7-10C)bicycloalkaneand (8-12C)tricycloalkane each optionally substituted on an availablecarbon atom, including the ring carbon atom bearing the Z-containinggroup, by one substituent selected from hydroxy, (1-4C)alkyl,(1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl;or Ring C is a di-linked (excluding links via the same or adjacentatoms) ring selected from phenylene, pryidindiyl, piperidinediylN-linked to Y₁, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl,thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl and pyrazoldiyl;each optionally substituted on an available carbon atom by up to foursubstituents independently selected from fluoro, chloro, bromo, cyano,(1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl;L is a direct bond to Ring C, —O—, —S— or —NH—;p is 0, 1 or 2 and when p is 1 R^(A1) and R^(A2) are each independentlyhydrogen or (1-4C)alkyl or R^(A1) and R^(A2) are linked together to forma (3-6C)spiroalkyl ring;Z is carboxy or a mimic or bioisostere thereof, hydroxy or —CONRbRcwherein Rb and Rc are independently selected from hydrogen and(1-4C)alkyl, which (1-4C)alkyl group may be optionally substituted bycarboxy or a mimic or bioisostere thereof;and wherein any carbon atom in a linear (1-3C)alkyl, (1-2C)alkoxy,(1-4C)alkyl or (1-4C)alkoxy containing group defined above may beoptionally substituted by up to 3 fluoro atoms.

In a further embodiment there is provided a compound of formula (I), ora pharmaceutically-acceptable salt, or pro-drug thereof, as in anyembodiment hereinbefore or hereinafter, with the proviso that thecompound (4-(4-(6-carbamoyl-pyridin-2-yl)phenyl)cyclohexyl)acetic acidis excluded.

A further feature is any of the above three embodiments with the provisothat any of the specific Examples herein are individually disclaimed.For example, a further feature is any of the above embodiments with theproviso that any of the compounds selected from the following areindividually disclaimed,{trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid;3,5-Dimethyl-6-[4-(trans-4-{2-[(methylsulfonyl)amino]-2-oxoethyl}cyclohexyl)-phenyl]pyrazine-2-carboxamide;6-{4-[trans-4-(2-Amino-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxamide;N-({trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}acetyl)-2-methylalanine;6-{4-[trans-4-(2-Hydroxyethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxamide;(trans-4-{-4-[6-Carbamoyl-5-(difluoromethyl)-3-methylpyrazin-2-yl]phenyl}cyclohexyl)aceticacid;{trans-4-[4-(6-Carbamoyl-3-ethyl-5-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid;{trans-4-[4-(6-Carbamoyl-5-ethyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid and{trans-4-[4-(6-Carbamoyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid; or a pharmaceutically-acceptable salt of any of these.

It will be understood that Ring B and Ring C as a di-linked ring or ringsystem excludes links to Y₁ and L via the same or adjacent atoms (i.e.−1,1- and -1,2-links are excluded).

It will be understood that Ring B is numbered clockwise towards Ring Cfrom the dominant heteroatom in Ring B.

When p is 0 the group Z is connected directly to direct bond L (i.e. Zis connected directly to Ring C and L is not —O—, —S— or —NH—); when pis 2 the group Z is connected as follows to L;

As used herein, the reference to carboxylic acid mimic or bioisostereincludes groups as defined in The Practice of Medicinal Chemistry,Wermuth C. G. Ed.: Academic Press: New York, 1996, p 203. Particularexamples of such groups include —SO₃H, —S(O)₂NHR¹³, S(O)₂NHC(O)R¹³,—CH₂S(O)₂R¹³, —C(O)NHS(O)₂R¹³, —C(O)NHOH, —C(O)NHCN, —CH(CF₃)OH,C(CF₃)₂OH, —P(O)(OH)₂ and groups of sub-formula (a)-(i′) below

where p in sub-formula (k) is 1 or 2, R²⁷ and R²⁸ are independentlyselected from hydrogen, hydroxy, (1-6C)alkoxy, thiol, (1-6C)alkylthio,—C(O)R²⁹, —S(O)R³⁰, —SO₂R³¹, —NR³²R³³, —NHCN, halogen and trihalomethyl,where R²⁹, R³⁰ and R³¹ are —OR³⁴, (1-6C)alkyl, —NR³²R³³ ortrihalomethyl, R³² and R³³ are independently selected from hydrogen,(1-6C)alkyl, —SO₂R³⁴ and —COR³⁵, where R³⁵ is (1-6C)alkyl ortrihalomethyl, and R³⁴ is hydrogen, (1-6C)alkyl or trihalomethyl and R¹³is selected from hydrogen, (1-6C)alkyl, hydroxy, halo, amino, cyano,((1-3C)alkyl)CONH—, carboxy, (1-6C)alkoxy, (1-6C)alkoxycarbonyl,carbamoyl, N-((1-6C)alkyl)carbamoyl, halo((1-6C)alkyl) (such astrifluoromethyl), (1-6C)alkylsulphonyl or (1-6C)alkylsulphinyl.Particular examples of R²⁷ or R²⁸ are hydroxy.

Particular carboxylic acid mimic or bioisosteres are a tetrazole groupof sub-formula (b) —C(O)NHS(O)₂Me.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups, unless otherwise stated, and references toindividual alkyl groups such as “propyl” are specific for the straightchain version only. An analogous convention applies to other genericterms. Unless otherwise stated the term “alkyl” advantageously refers tochains with 1-10 carbon atoms, suitably from 1-6 carbon atoms,preferably 1-4 carbon atoms.

In this specification the term “alkoxy” means an alkyl group as definedhereinbefore linked to an oxygen atom.

Particular values include for linear (1-3C)alkyl, methyl, ethyl andpropyl; for (1-4C)alkyl, methyl, ethyl, propyl and butyl; for(2-3C)alkenyl, ethenyl; for (2-3C)alkynyl, ethynyl; for (1-2C)alkoxy,methoxy and ethoxy; for (1-4C)alkoxy, methoxy, ethoxy and propoxy; for—CONRbRc, —CONH₂ and —CONHMe.

Particular values include for any carbon atom in a linear (1-3C)alkyl,(1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy group that may be optionallysubstituted by up to 3 fluoro atoms, a group such as, for example,trifluoromethyl, difluoromethyl, difluoromethoxy or trifluoromethoxy.

When p in formula (I) is 1 and R^(A1) and R^(A2) are linked together toform a (3-6C)spiroalkyl ring, such a ring may be, for example, aspiro-linked cyclopropyl or cyclobutyl.

When p in formula (I) is 2 and R^(A1) and R^(A2) are linked together toform a (3-6C)spiroalkyl ring, such a ring may be, for example, aspino-linked cyclopropyl or cyclobutyl.

When Ring C is a di-linked (excluding links via the same or adjacentatoms) (4-6C)cycloalkane ring this includes 1,4-cyclohexane,1,3-cyclopentane and 1,3-cyclobutane.

When Ring C is (7-10C)bicycloalkanediyl this includesbicyclo[2.2.1]heptanediyl, 1,4-bicyclo[2.2.2]octanediyl,1,5-bicyclo[3.2.1]octanediyl, 1,5-bicyclo[3.2.2]nonanediyl and1,5-bicyclo[3.3.2]decanediyl.

When Ring C is (8-12C)tricycloalkanediyl this includes adamantanediyl.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’ or ‘definedhereinbefore’ the said group encompasses the first occurring andbroadest definition as well as each and all of the particulardefinitions for that group.

If not stated elsewhere, suitable optional substituents for a particulargroup are those as stated for similar groups herein.

A compound of formula (I) may form stable acid or basic salts, and insuch cases administration of a compound as a salt may be appropriate,and pharmaceutically acceptable salts may be made by conventionalmethods such as those described following.

Suitable pharmaceutically-acceptable salts include acid addition saltssuch as methanesulfonate, tosylate, α-glycerophosphate, fumarate,hydrochloride, citrate, maleate, tartrate and (less preferably)hydrobromide. Also suitable are salts formed with phosphoric andsulfuric acid. In another aspect suitable salts are base salts such asGroup (I) (alkali metal) salt, Group (II) (alkaline earth) metal salt,an organic amine salt for example triethylamine, morpholine,N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine,N,N-dibenzylethylamine, tris-(2-hydroxyethyl)amine, N-methyl d-glucamineand amino acids such as lysine. There may be more than one cation oranion depending on the number of charged functions and the valency ofthe cations or anions.

Other suitable pharmaceutically-acceptable salts are mentioned in, forexample, Berge et al. (J. Pharm. Sci., 1977, 66, 1-19) and/or Handbookof Pharmaceutical Salts: Properties, Selection and Use by Stahl andWermuth (Wiley-VCH, 2002).

A feature of the invention relates to a compound of the invention, suchas any one of the Examples, in the free acid or free base form or as apharmaceutically acceptable salt thereof. Such forms may be prepared bystandard techniques.

However, to facilitate isolation of the salt during preparation, saltswhich are less soluble in the chosen solvent may be preferred whetherpharmaceutically-acceptable or not.

Within the present invention it is to be understood that a compound ofthe formula (I) or a salt thereof may exhibit the phenomenon oftautomerism and that the formulae drawings within this specification canrepresent only one of the possible tautomeric forms. It is to beunderstood that the invention encompasses any tautomeric form whichinhibits DGAT1 activity and is not to be limited merely to any onetautomeric form utilised within the formulae drawings.

Pro-drugs of compounds of formula (I), and salts thereof, are alsowithin the scope of the invention.

Various forms of prodrugs are known in the art. For examples of suchprodrug derivatives, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985);b) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application ofProdrugs”, by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);and e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

Examples of such prodrugs are in vivo cleavable esters of a compound ofthe invention. An in vivo cleavable ester of a compound of the inventioncontaining a carboxy group is, for example, apharmaceutically-acceptable ester which is cleaved in the human oranimal body to produce the parent acid. Suitablepharmaceutically-acceptable esters for carboxy include (1-6C)alkylesters, for example methyl or ethyl; (1-6C)alkoxymethyl esters, forexample methoxymethyl; (1-6C)alkanoyloxymethyl esters, for examplepivaloyloxymethyl; phthalidyl esters;(3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters, for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters, forexample 5-methyl-1,3-dioxolan-2-ylmethyl; (1-6C)alkoxycarbonyloxyethylesters, for example 1-methoxycarbonyloxyethyl; aminocarbonylmethylesters and mono- or di-N-((1-6C)alkyl) versions thereof, for exampleN,N-dimethylaminocarbonylmethyl esters and N-ethylaminocarbonylmethylesters; and may be formed at any carboxy group in the compounds of thisinvention. An in vivo cleavable ester of a compound of the inventioncontaining a hydroxy group is, for example, apharmaceutically-acceptable ester which is cleaved in the human oranimal body to produce the parent hydroxy group. Suitablepharmaceutically acceptable esters for hydroxy include (1-6C)alkanoylesters, for example acetyl esters; and benzoyl esters wherein the phenylgroup may be substituted with aminomethyl or N— substituted mono- ordi-(1-6C)alkyl aminomethyl, for example 4-aminomethylbenzoyl esters and4-N,N-dimethylaminomethylbenzoyl esters.

Particular prodrugs are (1-4C)alkyl esters of the carboxylic acid incompounds of formula (I), (IA) and/or (IB).

It will be appreciated by those skilled in the art that certaincompounds of formula (I) contain asymmetrically substituted carbonand/or sulfur atoms, and accordingly may exist in, and be isolated in,optically-active and racemic forms. Some compounds of formula (I) mayexhibit polymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic or stereoisomericform, or mixtures thereof, which form possesses properties useful in theinhibition of DGAT1 activity, it being well known in the art how toprepare optically-active forms (for example, by resolution of theracemic form by recrystallization techniques, by synthesis fromoptically-active starting materials, by chiral synthesis, by enzymaticresolution, by biotransformation, or by chromatographic separation usinga chiral stationary phase) and how to determine efficacy for theinhibition of DGAT1 activity by the standard tests describedhereinafter.

It is also to be understood that certain compounds of the formula (I)and salts thereof can exist in solvated as well as unsolvated forms suchas, for example, hydrated forms. It is to be understood that theinvention encompasses all such solvated forms which inhibit DGAT1activity.

As stated before, a range of compounds are provided that have good DGAT1inhibitory activity. They have good physical and/or pharmacokineticproperties in general.

Thus, in one embodiment there is provided a compound of formula (I), ora pharmaceutically-acceptable salt thereof,

whereinRing A is 2,6-pyrazindiyl, 3,5-pyridindiyl or 2,6-pyridindiyl, eachoptionally substituted on an available carbon atom by one or twosubstituents independently selected from linear (1-3C)alkyl,(2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino andcyano;

X is ═O or ═S;

Ring B is 1,4-phenylene or Ring B is a di-linked (excluding links viathe same or adjacent atoms) ring selected from pyridindiyl, furandiyl,thiophendiyl, pyrroldiyl, oxazoldiyl, thiazoldiyl, imidazoldiyl,isoxazoldiyl, isothiazoldiyl and pyrazoldiyl; each optionallysubstituted on an available carbon atom by one or two substituentsindependently selected from halo, amino, cyano, (1-4C)alkyl,(2-3C)alkenyl, (2-3C)alkynyl, (1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl;Y₁ is a direct bond between Ring B and Ring C or Y₁ is —O—, —S— or —NRa—wherein Ra is hydrogen or (1-4C)alkyl;Y₂ is —(CH₂)_(r)— wherein r is 2 or 3, and Y₂ is linked at the samecarbon atom as Y₁ in RingC and Y₂ is linked at an adjacent carbon atom to Y₁ in Ring B;n is 0 or n is 1 when Y₁ is a direct bond between Ring B and Ring C andwhen Ring B is 1,4-phenylene and Ring C is (4-6C)cycloalkane, so that a5- or 6-membered spiro-ring system is formed and Ring C is tri-linked;Ring C is a di-linked (excluding links via the same or adjacent atoms)ring or ring system chosen from (4-6C)cycloalkane, (7-10C)bicycloalkaneand (8-12C)tricycloalkane each optionally substituted on an availablecarbon atom, including the ring carbon atom bearing the Z-containinggroup, by one substituent selected from hydroxy, (1-4C)alkyl,(1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl;or Ring C is a di-linked (excluding links via the same or adjacentatoms) ring selected from phenylene, pryidindiyl, piperidinediylN-linked to Y₁, piperazinediyl, furandiyl, thiophendiyl, pyrroldiyl,oxazoldiyl, thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl,pyrazoldiyl and azabicyclo[3.1.0]hexanediyl;each optionally substituted on an available carbon atom by up to foursubstituents independently selected from fluoro, chloro, bromo, cyano,(1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl;L is a direct bond to Ring C, —O—, —S— or —NH—;p is 0, 1 or 2 and when p is 1 R^(A1) and R^(A2) are each independentlyhydrogen or (1-4C)alkyl or R^(A1) and R^(A2) are linked together to forma (3-6C)spiroalkyl ring;Z is carboxy or a mimic or bioisostere thereof, hydroxy or —CONRbRcwherein Rb and Rc are independently selected from hydrogen and(1-4C)alkyl, which (1-4C)alkyl group may be optionally substituted bycarboxy or a mimic or bioisostere thereof;and wherein any carbon atom in a linear (1-3C)alkyl, (1-2C)alkoxy,(1-4C)alkyl or (1-4C)alkoxy containing group defined above may beoptionally substituted by up to 3 fluoro atoms; with the proviso thatthe compound (4-(4-(6-Carbamoyl-pyridin-2-yl)phenyl)cyclohexyl)aceticacid is excluded.

In another embodiment there is provided a compound of formula (I), or apharmaceutically-acceptable salt, or pro-drug thereof wherein

Ring A is 2,6-pyrazindiyl, 3,5-pyridindiyl or 2,6-pyridindiyl, eachoptionally substituted on an available carbon atom by one or twosubstituents independently selected from linear (1-3C)alkyl,(2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino andcyano;

X is ═O or ═S;

Ring B is 1,4-phenylene or Ring B is a di-linked (excluding links viathe same or adjacent atoms) ring selected from pyridindiyl, furandiyl,thiophendiyl, pyrroldiyl, oxazoldiyl, thiazoldiyl, imidazoldiyl,isoxazoldiyl, isothiazoldiyl and pyrazoldiyl; each optionallysubstituted on an available carbon atom by one or two substituentsindependently selected from halo, amino, cyano, (1-4C)alkyl,(2-3C)alkenyl, (2-3C)alkynyl, (1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl;Y₁ is a direct bond between Ring B and Ring C or Y₁ is —O—, —S— or —NRa—wherein Ra is hydrogen or (1-4C)alkyl;Y₂ is —(CH₂)_(r)— wherein r is 2 or 3, and Y₂ is linked at the samecarbon atom as Y₁ in Ring C and Y₂ is linked at an adjacent carbon atomto Y₁ in Ring B;n is 0 or n is 1 when Y₁ is a direct bond between Ring B and Ring C andwhen Ring B is 1,4-phenylene and Ring C is (4-6C)cycloalkane, so that a5- or 6-membered spiro-ring system is formed;Ring C is a di-linked (excluding links via the same or adjacent atoms)ring or ring system chosen from (4-6C)cycloalkane, (7-10C)bicycloalkaneand (8-12C)tricycloalkane each optionally substituted on an availablecarbon atom, including the ring carbon atom bearing the Z-containinggroup, by one substituent selected from hydroxy, (1-4C)alkyl,(1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl;or Ring C is a di-linked (excluding links via the same or adjacentatoms) ring selected from phenylene, pryidindiyl, piperidinediylN-linked to Y₁, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl,thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl and pyrazoldiyl;each optionally substituted on an available carbon atom by up to foursubstituents independently selected from fluoro, chloro, bromo, cyano,(1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl;L is a direct bond to Ring C, —O—, —S— or —NH—;p is 0, 1 or 2 and when p is 1 R^(A1) and R^(A2) are each independentlyhydrogen or (1-4C)alkyl or R^(A1) and R^(A2) are linked together to forma (3-6C)spiroalkyl ring;Z is carboxy or a mimic or bioisostere thereof, hydroxy or —CONRbRcwherein Rb and Rc are independently selected from hydrogen and(1-4C)alkyl, which (1-4C)alkyl group may be optionally substituted bycarboxy or a mimic or bioisostere thereof;and wherein any carbon atom in a linear (1-3C)alkyl, (1-2C)alkoxy,(1-4C)alkyl or (1-4C)alkoxy containing group defined above may beoptionally substituted by up to 3 fluoro atoms.

In another embodiment there is provided a compound of formula (IA), or apharmaceutically-acceptable salt, or pro-drug thereof,

wherein X, Ring A, Ring B, Y₁, p, R^(A1), R^(A2) and Z are as defined inclaim 1 or 2.

In another embodiment there is provided a compound of formula (IB), or apharmaceutically-acceptable salt, or pro-drug thereof,

wherein X, Ring A, Ring B, Y₁, p, R^(A1), R^(A2) and Z are as defined inclaim 1 or 2.

In another embodiment there is provided a compound as claimed in any oneof claims 1 to 4, or a pharmaceutically-acceptable salt, or pro-drugthereof, wherein X is ═O; Ring A is 2,6-pyrazindiyl optionallysubstituted on an available carbon atom by one or two substituentsindependently selected from linear (1-3C)alkyl, (2-3C)alkenyl,(2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino and cyano;

Ring B is 1,4-phenylene optionally substituted on an available carbonatom by one or two substituents independently selected from halo, amino,cyano, (1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-4C)alkoxy and(1-4C)alkoxy-(1-4C)alkyl;Ring C is 1,4-cyclohexane;n is 0 and Y₁ is a direct bond or Y₁ is —O—;L is a direct bond;p is 1 and R^(A1) and R^(A2) are each hydrogen;Z is carboxy, a tetrazole group, —C(O)NHS(O)₂Me, hydroxy or —CONRbRcwherein Rb and Rc are independently selected from hydrogen and(1-4C)alkyl, which (1-4C)alkyl group may be optionally substituted bycarboxy; and wherein any carbon atom in a linear (1-3C)alkyl,(1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy containing group defined abovemay be optionally substituted by up to 3 fluoro atoms.

In another embodiment there is provided a compound as claimed in any oneof claims 1 to 5, or a pharmaceutically-acceptable salt, or pro-drugthereof, wherein Ring A is 2,6-pyrazindiyl optionally substituted on anavailable carbon atom by one or two linear (1-3C)alkyl substituents.

The following compounds possess particular, desirable pharmaceuticaland/or physical and/or pharmacokinetic/dynamic and/or toxicologicalproperties and/or selective activity for DGAT1.

A compound of formula (I), or a pharmaceutically-acceptable salt, orpro-drug thereof,

whereinRing A is 2,6-pyrazindiyl, 3,5-pyridindiyl or 2,6-pyridindiyl, eachoptionally substituted on an available carbon atom by one or twosubstituents independently selected from linear (1-3C)alkyl,(2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino andcyano;

X is ═O or ═S;

Ring B is 1,4-phenylene or Ring B is a di-linked (excluding links viathe same or adjacent atoms) pyridindiyl ring; each optionallysubstituted on an available carbon atom by one or two substituentsindependently selected from halo, amino, cyano, (1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl;Y₁ is a direct bond between Ring B and Ring C or Y₁ is —O—, —S— or —NRa—wherein Ra is hydrogen or (1-4C)alkyl;n is 0;Ring C is a di-linked (excluding links via the same or adjacent atoms)(4-6C)cycloalkane ring, optionally substituted on an available carbonatom, including the ring carbon atom bearing the Z-containing group, byone substituent selected from hydroxy, (1-4C)alkyl, (1-4C)alkoxy and(1-4C)alkoxy(1-4C)alkyl;L is a direct bond to Ring C or —O—;p is 0, 1 or 2 and when p is 1 R^(A1) and R^(A2) are each independentlyhydrogen or (1-4C)alkyl;Z is carboxy or a mimic or bioisostere thereof, hydroxy or —CONRbRcwherein Rb and Rc are independently selected from hydrogen and(1-4C)alkyl, which (1-4C)alkyl group may be optionally substituted bycarboxy or a mimic or bioisostere thereof;and wherein any carbon atom in a linear (1-3C)alkyl, (1-2C)alkoxy,(1-4C)alkyl or (1-4C)alkoxy containing group defined above may beoptionally substituted by up to 3 fluoro atoms.

In one aspect, it will be appreciated that in certain compounds offormula (I) the Ring C substituent bearing the Z group (or suitablereplacement thereof) and the —Y₁— link are in either a cis- or atrans-arrangement across the ring, in relation to each other. Whereappropriate the invention encompasses both the cis- and trans-isomers.Techniques for separation of such isomers are well known in the art.

Thus, in one aspect, when Ring C is cyclohexyl the Z containing groupand —Y₁— link are in a cis-configuration across the cyclohexyl ring, togive a compound of formula (IA), wherein the variables are as definedhereinbefore or hereinafter:

Thus, in one aspect, when Ring C is cyclohexyl the Z containing groupand —Y₁— link are in a trans-configuration across the cyclohexyl ring,to give a compound of formula (IB), wherein the variables are as definedhereinbefore or hereinafter:

References hereinbefore or hereinafter to a compound of formula (I) aretaken to apply also to compounds of formulae (IA) and (IB).

In one embodiment of the invention there are provided compounds offormulae (I), (IA) and (IB), in an alternative embodiment there areprovided salts, particularly pharmaceutically-acceptable salts ofcompounds of formulae (I), (IA) and (IB). In a further embodiment, thereare provided pro-drugs, particularly in-vivo cleavable esters, ofcompounds of formulae (I), (IA) and (IB). In a further embodiment, thereare provided salts, particularly pharmaceutically-acceptable salts ofpro-drugs of compounds of formulae (I), (IA) and (IB).

Particular values of substituents in compounds of formulae (I), (IA) and(IB) are as follows (such values may be used where appropriate with anyof the other values, definitions, claims or embodiments definedhereinbefore or hereinafter).

-   1) X is ═O;-   2) X is ═S;-   3) Ring A is 2,6-pyrazindiyl;-   4) Ring A is 2,6-pyrazindiyl substituted with any of the    substituents in the Examples;-   5) Ring A is 2,6-pyrazindiyl substituted with one or two    (1-3C)alkyl;-   6) Ring B is 1,4-phenylene;-   7) Ring B is 2,5-pyridindiyl or 3,6-pyridindiyl;-   8) Ring B is optionally substituted on an available carbon atom by    one or two halo substituents;-   9) Ring C is 1,4-cyclohexane (i.e. 1,4-cyclohexyl);-   10) n is 0 and Y₁ is a direct bond between Ring B and Ring C or Y₁    is —O—;-   11) Ring B and Ring C are particularly 2,4- or 2,5-furandiyl, 2,4-    or 2,5-thiophendiyl, 2,4- or 2,5-pyrroldiyl, 2,4- or 2,5-oxazoldiyl,    2,4- or 2,5-thiazoldiyl, 2,4- or 2,5-imidazoldiyl, 3,4- or    3,5-isoxazoldiyl, 3,4- or 3,5-isothiazoldiyl, 3,4- or    3,5-pyrazoldiyl;-   12) L is a direct bond;-   13) p is 0;-   14) p is 1 and R^(A1) and R^(A2) are each hydrogen;-   15) p is 2 and R^(A1) and R^(A2) are each hydrogen;-   16) Z is carboxy, —CONRbRc (wherein Rb and Rc are independently    selected from hydrogen and (1-4C)alkyl (which (1-4C)alkyl group may    be optionally substituted by carboxy), a tetrazole group or    —C(O)NHS(O)₂Me;-   17) Z is carboxy;-   18) a pro-drug for Z as carboxy is a (1-6C)alkyl ester.

Thus, for example, in one embodiment there is provided a compound offormula (I), or a pharmaceutically-acceptable salt thereof, wherein X═O;Ring A is 2,6-pyrazindiyl optionally substituted on an available carbonatom by one or two substituents independently selected from linear(1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl,amino and cyano; Ring B is 1,4-phenylene (optionally substituted on anavailable carbon atom by one or two halo substituents); n is 0 and Y₁ isa direct bond between Ring B and Ring C; p is 0 or p is 1 and R^(A1) andR^(A2) are each hydrogen; L is a direct bond and Z is carboxy, —CONRbRc(wherein Rb and Rc are independently selected from hydrogen and(1-4C)alkyl (which (1-4C)alkyl group may be optionally substituted bycarboxy), a tetrazole group or —C(O)NHS(O)₂Me; i.e. a compound offormula (IC), or a pharmaceutically-acceptable salt thereof, wherein the2,6-pyrazindiyl ring is optionally substituted on an available carbonatom by one or two substituents independently selected from linear(1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl,amino and cyano and other values are as defined immediately above.

In another embodiment there is provided a compound of formula (I), or apharmaceutically-acceptable salt thereof, wherein X═O; Ring A is2,6-pyrazindiyl optionally substituted on an available carbon atom byone or two substituents independently selected from linear (1-3C)alkyl,(2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino andcyano; Ring B is 1,4-phenylene (optionally substituted on an availablecarbon atom by one or two halo substituents); n is 0 and Y₁ is a directbond between Ring B and Ring C; p is 1 and R^(A1) and R^(A2) are eachhydrogen; L is a direct bond and Z is carboxy or a tetrazole group.

In another embodiment there is provided a compound of formula (I), or apharmaceutically-acceptable salt thereof, wherein X═O; Ring A is2,6-pyrazindiyl optionally substituted on an available carbon atom byone or two substituents independently selected from linear (1-3C)alkyl;Ring B is 1,4-phenylene (optionally substituted on an available carbonatom by one or two fluoro substituents); n is 0 and Y₁ is a direct bondbetween Ring B and Ring C; p is 1 and R^(A1) and R^(A2) are eachhydrogen; L is a direct bond and Z is carboxy or a tetrazole group.

In another embodiment there is provided a compound of formula (I), or apharmaceutically-acceptable salt thereof, wherein X═O; Ring A is2,6-pyrazindiyl optionally substituted on an available carbon atom byone or two methyl substituents; Ring B is 1,4-phenylene (optionallysubstituted on an available carbon atom by one or two fluorosubstituents); n is 0 and Y₁ is a direct bond between Ring B and Ring C;p is 1 and R^(A1) and R^(A2) are each hydrogen; L is a direct bond and Zis carboxy or a tetrazole group.

In another embodiment there is provided a compound of formula (I), or apharmaceutically-acceptable salt thereof, wherein X═O; Ring A is2,6-pyrazindiyl optionally substituted on an available carbon atom byone or two methyl substituents; Ring B is 1,4-phenylene; n is 0 and Y₁is a direct bond between Ring B and Ring C; p is 1 and R^(A1) and R^(A2)are each hydrogen; L is a direct bond and Z is carboxy or a tetrazolegroup.

In another embodiment there is provided a compound of formula (I), or apharmaceutically-acceptable salt thereof, wherein X═O; Ring A is2,6-pyrazindiyl optionally substituted on an available carbon atom byone or two methyl substituents; Ring B is 1,4-phenylene; n is 0 and Y₁is a direct bond between Ring B and Ring C; p is 1 and R^(A1) and R^(A2)are each hydrogen; L is a direct bond and Z is carboxy.

In another embodiment there is provided a compound of formula (I),wherein X═O; Ring A is 2,6-pyrazindiyl optionally substituted on anavailable carbon atom by one or two methyl substituents; Ring B is1,4-phenylene; n is 0 and Y₁ is a direct bond between Ring B and Ring C;p is 1 and R^(A1) and R^(A2) are each hydrogen; L is a direct bond and Zis carboxy.

In another embodiment there is provided a compound of formula (I) asdefined in any of the seven embodiments immediately above, wherein the Zcontaining group and the —Y₁— link are in either a cis- or atrans-arrangement across the ring, in relation to each other.

In another embodiment there is provided a compound of formula (I) asdefined in any of the eight embodiments immediately above wherein apro-drug for Z as carboxy is a (1-6C)alkyl ester.

A further feature is any of the scopes defined herein with the provisothat specific Examples, such as Example 1, 2, 3, 4 etc. are individuallydisclaimed.

Further particular compounds of the invention are each of the Examples,each of which provides a further independent aspect of the invention. Infurther aspects, the present invention also comprises any particularcompounds of the Examples or a pharmaceutically-acceptable salt thereof(such as, for example, a sodium, magnesium, tert-butylammonium,tris(hydroxymethyl)methylammonium, triethanolammonium,diethanolammonium, ethanolammonium, methylethanolammonium,diethylammonium or nicotinamide salt).

For example, a further feature is any of the particular compounds of theExamples or a pharmaceutically-acceptable salt thereof, such as anycompound selected from{trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid;3,5-Dimethyl-6-[4-(trans-4-{2-[(methylsulfonyl)amino]-2-oxoethyl}cyclohexyl)-phenyl]pyrazine-2-carboxamide;6-{4-[trans-4-(2-Amino-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxamide;N-({trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}acetyl)-2-methylalanine;6-{4-[trans-4-(2-Hydroxyethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxamide;(trans-4-{4-[6-Carbamoyl-5-(difluoromethyl)-3-methylpyrazin-2-yl]phenyl}cyclohexyl)aceticacid;{trans-4-[4-(6-Carbamoyl-3-ethyl-5-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid;{trans-4-[4-(6-Carbamoyl-5-ethyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid;{trans-4-[4-(6-Carbamoyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid;2-((1r,4s)-5′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-yl)aceticacid;(1r,4s)-5′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carboxylicacid;2-((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)-2-methylpropanoicacid2-(1-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)pyrrolidin-3-yl)aceticacid;(1R,5S,6r)-3-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid;6-(4-((1r,4r)-4-((1H-Tetrazol-5-yl)methyl)cyclohexyl)phenyl)-3,5-dimethylpyrazine-2-carboxamide;4′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)biphenyl-4-carboxylic acid;Methyltrans-4-{4-[6-(aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}-cyclohexanecarboxylate;trans-4-{4-[6-(Aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}cyclo-hexanecarboxylicacid; or a pharmaceutically-acceptable salt of any of these.

In a further aspect, the present invention also comprises any particularisomers of compounds of the Examples, such as the cis-isomer ofcompounds such as Examples 1 or 2, i.e.{cis-4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid or3,5-dimethyl-6-[4-(cis-4-{2-[(methylsulfonyl)amino]-2-oxoethylcyclohexyl)phenyl]-pyrazine-2-carboxamideor a pharmaceutically-acceptable salt of either of these; or compoundssuch as6-{4-[cis-4-(2-Amino-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxamide;N-({cis-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenylcyclohexyl}acetyl]-2-methylalanine;6-{4-[cis-4-(2-Hydroxyethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxamide;(cis-4-{4-[6-Carbamoyl-5-(difluoromethyl)-3-methylpyrazin-2-yl]phenyl}cyclohexyl)aceticacid;{cis-4-[4-(6-Carbamoyl-3-ethyl-5-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid;{cis-4-[4-(6-Carbamoyl-5-ethyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid;{cis-4-[4-(6-Carbamoyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid; or a pharmaceutically-acceptable salt of any of these.

A compound of formula (I) and its salts may be prepared by any processknown to be applicable to the preparation of chemically relatedcompounds. Such processes, when used to prepare a compound of theformula (I), or a pharmaceutically-acceptable salt thereof, are providedas a further feature of the invention.

In a further aspect the present invention also provides that thecompounds of the formula (I) and salts thereof, can be prepared by thefollowing processes, the processes of the Examples and analogousprocesses (wherein all variables are as hereinbefore defined for acompound of formula (I) unless otherwise stated) and thereafter ifnecessary any protecting groups can be removed and/or an appropriatesalt formed. Any defined carboxylic acid groups may be replaced asappropriate by a mimic or bioisostere thereof.

Variables shown in the schemes are defined or can be interpreted in thecontext of the variants described herein for the compounds of theinvention. Analogous chemistry to that shown in the schemes and Examplesmay be used to prepare other ring variants and linking group optionswithin the scope of the invention.

Also included as an aspect of the invention are the compounds obtainableby any of the processes or Examples described herein.

Process a)

By modifying a substituent in, or introducing a substituent into,another compound of formula (I). Suitable methods for convertingsubstituents into other substituents are known in the art. For example,an acid group may be converted into an amide group or reduced to analcohol group.

An amide in Ring A may be converted into a thioamide by use ofLawesson's reagent or P₂S₅.

Compounds of formula (I) where, for example, Z is an acylsulfonamidegroup or Z is a tetrazole may be prepared from the correspondingcarboxylic acid. The tetrazole may be introduced early in the syntheticroute via an amide (which, for primary amides, may be converted to thenitrile by standard methods) which is then in turn converted into atetrazole by reaction with azide. The tetrazole may be carried throughthe rest of the synthesis in protected form, e.g. N-benzylated orN-(2-cyanoethyl)ated.

Process b)

Suzuki coupling of an appropriate iodo-, bromo- or chloro-substitutedRing A derivative (e.g. pyrazine ester (III)) with a suitablysubstituted intermediate boronate compound of formula (II) followed byconversion of the ring A ester group to the corresponding acid by basichydrolysis and thence to the corresponding primary carboxamide byreaction with ammonia in the presence of a coupling agent, for examplePyBOP.

A protecting group can be removed, for example, by acid catalysedhydrolysis of a tert-butyl ester to give a compound of formula (I) whereZ═CO₂H.

R and R′ may represent any of the variables defined herein at suchpositions.

Analogous chemistry may be used to prepare other Ring A derivatives(e.g. pyridine compounds).

Alternatively a Suzuki coupling of an appropriate iodo-, bromo- orchloro-pyrazine amide (IV), particularly bromo- or chloro-pyrazine amide(IV), can be used followed by removal of the protecting group by basichydrolysis of a methyl or ethyl ester.

Preparation of Formula (III) Compound Types (Ring A)

The following schemes illustrate how certain Ring A variants may beprepared. Variables shown in the schemes are defined or can beinterpreted in the context of the variants described herein for thecompounds of the invention. Analogous chemistry to that shown in theschemes and Examples may be used to prepare other Ring variants andlinking group options within the scope of the invention.

Preparation of Formula (III) and (Iv) Compound Types (Ring A)

Analogues of pyrazine can be prepared using the procedure described byC. Christensen, C. W. Tomoe and M. Meldal, QSAR & Combinatorial Science,2004, 23, (2-3), 109-116, for example, 3-methylpyrazine . . .

Preparation of Formula (II) Compound Types (Ring C and Ring B)

The following schemes illustrate how certain Ring C and Ring B variantsmay be prepared. Variables shown in the schemes are defined or can beinterpreted in the context of the variants described herein for thecompounds of the invention. Analogous chemistry to that shown in theschemes and Examples may be used to prepare other ring variants andlinking group options within the scope of the invention.(i) Compounds of formula (II) in which Ring C is cyclohexane (p is 2 instructure C1) and Ring B is phenyl are described in the literature orcan be made by analogy. These may be brominated to (C2) and thenconverted into the boronate esters (C3) using standard procedures.Alternative leaving groups to bromo in (C2) are iodo and triflate (seeScheme C1-B).

Scheme C1-B methyl ester has been described in WO 2004/047755.

Compounds in which a bromo-heteroaryl compound is required may not bedirectly obtainable via the unsubstituted heteroaryl compound. The bromogroup, or other suitable alternative, may be introduced at an earlierstage in the synthetic route.

(ii) For compounds of formula (II) in which Ring C is phenyl and Ring Bis phenyl many appropriate intermediates are in the literature, or canbe made by analogy, and introduction of various substitution patternsmay be achieved through biaryl Suzuki coupling:

In Scheme C2, R and R′ are any of the claimed aromatic substituentswhich are compatible with the reaction conditions, X is a suitableleaving group such as bromo, iodo or triflate. The bromobiaryl is thenconverted into the corresponding boronate derivative by standardmethods.

For both Scheme C1 and C2, introduction of α-alkyl and dialkyl groups ispossible at the intermediate C1 or C2 stage through standard alkylationmethodology, for example by deprotonation α-to the ester group using alithium base such as LDA followed by quenching with an appropriate alkylhalide.

Preparation of Formula (V) Compound Types (Ring A and Ring B)

(i) In an alternative sequence of Suzuki couplings acyanoheterocyclylphenylboronic ester of type V is generated as a keyintermediate, as illustrated by the scheme below. This intermediate isthen used in further coupling reactions to generate biaryl compounds ofthe formula I.

In Scheme C2, R and R′ are any of the claimed aromatic substituentswhich are compatible with the reaction conditions. The phenol isconverted into the corresponding triflate with trifluoromethanesulfonicanhydride and a suitable base, such as triethylamine, which also resultsin dehydration of the amide to the nitrile. The aryltriflate isconverted to the corresponding boronate derivative followed bysubsequent Suzuki reaction under standard methods with a suitablepalladium catalyst, such as1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II). Basehydrolysis, for example with potassium hydroxide in tert-butanol resultsin hydrolysis of the ester and nitrile.

In Scheme C2-B, R and R′ are any of the claimed aromatic substituentswhich are compatible with the reaction conditions.(ii) Spirocyclic compounds of formula (II) may be prepared by analogywith preparations involving the intermediates in Scheme C4 below (see WO2004/047755—relevant sections of which are hereby incorporated byreference).

The double bond may be reduced at a suitable stage in the synthesis andthe resultant cis- and trans-isomers separated chromatographically. Asabove, this route may proceed by conversion of the bromo into theboronate for coupling to the appropriate Ring A (e.g. pyrazine)compound.

The cyclohexanone may be converted to the unsaturated ketone and thedouble bond reduced at a suitable stage in the synthesis and the cis-and trans-isomers separated chromatographically. Alternatively thecyclohexane may be converted to the aldehyde which can be oxidised tothe acid, for example with oxone and the acid converted to an ester, forexample a tert-butyl and the cis- and trans-isomers separatedchromatographically. As above, this route may proceed by conversion ofthe bromo into the boronate for coupling to the appropriate Ring A (e.g.pyrazine) compound.

For compounds of the formula (V) in which Ring B is Phenyl and Ring C isa cyclic amine, introduction of the amine maybe achieved throughtransition metal coupling.

In Scheme C5 the amines may be introduced using boronic acids or estersusing copper acetate as in the procedure described by D. M. T. Chan, K.L Monaco, R. Li, D. Bonne, C. G. Clark, P. Y. S Lam, Tet. Lett., 2003,44(19), 3863-3865.

(iii) Bicyclooctane derivatives of formula (II) may be prepared byanalogy with preparations involving the phenyl Intermediate C5 below(see WO 2007/071966—relevant sections of which are hereby incorporatedby reference), which is brominated and converted into the boronate forcoupling to the appropriate Ring A (e.g. pyrazine) compound.

Compounds of formula C5 may be made as their ester derivative accordingto the process shown below in Scheme C3, or analogously thereto.

Compounds such as C6 may be homologated by standard procedures such asreduction of the ester to the corresponding alcohol, conversion of thisto a leaving group such as tosylate, displacing this with cyanidefollowed by hydrolysis and esterification, all by standard methods, tocompounds such as C5 wherein n=1.

Compounds in which Ring C is other than bicyclo[2.2.2]octane-1,4-diylmay be prepared by analogous processes.

Adamantyl derivatives of formula (II) may be prepared by analogy withpreparations involving the phenyl Intermediate C7 below (see WO2007/071966—relevant sections are hereby incorporated by reference),which is iodinated and converted to the boronate for coupling to theappropriate Ring A (e.g. pyrazine).

If not commercially available, the necessary starting materials for theprocedures such as those described above may be made by procedures whichare selected from standard organic chemical techniques, techniques whichare analogous to the synthesis of known, structurally similar compounds,techniques which are described or illustrated in the references givenabove, or techniques which are analogous to the above describedprocedure or the procedures described in the examples. The reader isfurther referred to Advanced Organic Chemistry, 5^(th) Edition, by JerryMarch and Michael Smith, published by John Wiley & Sons 2001, forgeneral guidance on reaction conditions and reagents.

It will be appreciated that some intermediates to compounds of theformula (I) are also novel and these are provided as separateindependent aspects of the invention. In particular, certain compoundsof formula (IV) may form a further independent aspect of the invention.Furthermore, ester derivatives of compounds of formula (I) form afurther aspect of the invention.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups incompounds. The instances where protection is necessary or desirable areknown to those skilled in the art, as are suitable methods for suchprotection. Conventional protecting groups may be used in accordancewith standard practice (for illustration see T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley and Sons, 1991).

Protecting groups may be removed by any convenient method as describedin the literature or known to the skilled chemist as appropriate for theremoval of the protecting group in question, such methods being chosenso as to effect removal of the protecting group with minimum disturbanceof groups elsewhere in the molecule.

Thus, if reactants include, for example, groups such as amino, carboxyor hydroxy it may be desirable to protect the group in some of thereactions mentioned herein.

Examples of a suitable protecting group for a hydroxy group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, anaroyl group, for example benzoyl, a silyl group such as trimethylsilylor an arylmethyl group, for example benzyl. The deprotection conditionsfor the above protecting groups will necessarily vary with the choice ofprotecting group. Thus, for example, an acyl group such as an alkanoylor an aroyl group may be removed, for example, by hydrolysis with asuitable base such as an alkali metal hydroxide, for example lithium orsodium hydroxide. Alternatively a silyl group such as trimethylsilyl orSEM may be removed, for example, by fluoride or by aqueous acid; or anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation in the presence of a catalyst such as palladium-on-carbon.

A suitable protecting group for an amino group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an alkoxycarbonylgroup, for example a methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulfuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

Resins may also be used as a protecting group.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art,or they may be removed during a later reaction step or work-up.

The skilled organic chemist will be able to use and adapt theinformation contained and referenced within the above references, andaccompanying Examples therein and also the examples herein, to obtainnecessary starting materials, and products.

The removal of any protecting groups and the formation of apharmaceutically-acceptable salt are within the skill of an ordinaryorganic chemist using standard techniques. Furthermore, details on thethese steps has been provided hereinbefore.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the above proceduresusing an optically active starting material (formed, for example, byasymmetric induction of a suitable reaction step), or by resolution of aracemic form of the compound or intermediate using a standard procedure,or by chromatographic separation of diastereoisomers (when produced).Enzymatic techniques may also be useful for the preparation of opticallyactive compounds and/or intermediates.

Similarly, when a pure regioisomer of a compound of the invention isrequired, it may be obtained by carrying out one of the above proceduresusing a pure regioisomer as a starting material, or by resolution of amixture of the regioisomers or intermediates using a standard procedure.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I),(IA) or (IB) as defined hereinbefore or a pharmaceutically-acceptablesalt thereof, in association with a pharmaceutically-acceptableexcipient or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

According to a further aspect of the present invention there is provideda compound of formula (I), (IA) and/or (IB), or a pharmaceuticallyacceptable salt, or a pro-drug thereof as defined hereinbefore for usein a method of treatment of the human or animal body by therapy.

We have found that compounds of the present invention inhibit DGAT1activity and are therefore of interest for their blood glucose-loweringeffects.

A further feature of the present invention is a compound of formula (I),(IA) and/or (IB), or a pharmaceutically-acceptable salt, or a pro-drugthereof for use as a medicament.

Conveniently this is a compound of formula (I), (IA) and/or (IB), or apharmaceutically-acceptable salt, or a pro-drug thereof, for (use as amedicament for) producing an inhibition of DGAT1 activity in awarm-blooded animal such as a human being.

Particularly this is a compound of formula (I), (IA) and/or (IB), or apharmaceutically-acceptable salt, or a pro-drug thereof, for (use as amedicament for) treating diabetes mellitus and/or obesity in awarm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is providedthe use of a compound of formula (I), (IA) and/or (IB), or apharmaceutically-acceptable salt, or a pro-drug thereof in themanufacture of a medicament for use in the production of an inhibitionof DGAT1 activity in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is providedthe use of a compound of formula (I), (IA) and/or (IB), or apharmaceutically-acceptable salt, or a pro-drug thereof in themanufacture of a medicament for use in the treatment of diabetesmellitus and/or obesity in a warm-blooded animal such as a human being.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I),(IA) and/or (IB) as defined hereinbefore, or apharmaceutically-acceptable salt, or a pro-drug thereof, in associationwith a pharmaceutically-acceptable excipient or carrier for use inproducing an inhibition of DGAT1 activity in an warm-blooded animal,such as a human being.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I),(IA) and/or (IB) as defined hereinbefore, or apharmaceutically-acceptable salt, or a pro-drug thereof, in associationwith a pharmaceutically-acceptable excipient or carrier for use in thetreatment of diabetes mellitus and/or obesity in an warm-blooded animal,such as a human being.

According to a further feature of the invention there is provided amethod for producing an inhibition of DGAT1 activity in a warm-bloodedanimal, such as a human being, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), (IA) and/or (IB), or a pharmaceutically-acceptable salt, ora pro-drug thereof as defined hereinbefore.

According to a further feature of the invention there is provided amethod of treating diabetes mellitus and/or obesity in a warm-bloodedanimal, such as a human being, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), (IA) and/or (IB), or a pharmaceutically-acceptable salt, ora pro-drug thereof as defined hereinbefore.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular disease state will necessarily bevaried depending on the host treated, the route of administration andthe severity of the illness being treated. Preferably a daily dose inthe range of 1-50 mg/kg is employed. In another embodiment a daily doseis in the range of 0.01-50 mg/kg, particularly 0.01-10 mg/kg, 0.01-1mg/kg or 0.01-0.1 mg/kg. However the daily dose will necessarily bevaried depending upon the host treated, the particular route ofadministration, and the severity of the illness being treated.Accordingly the optimum dosage may be determined by the practitioner whois treating any particular patient.

As stated above compounds defined in the present invention are ofinterest for their ability to inhibit the activity of DGAT1. A compoundof the invention may therefore be useful for the prevention, delay ortreatment of a range of disease states including diabetes mellitus, morespecifically type 2 diabetes mellitus (T2DM) and complications arisingthere from (for example retinopathy, neuropathy and nephropathy),impaired glucose tolerance (IGT), conditions of impaired fastingglucose, metabolic acidosis, ketosis, dysmetabolic syndrome, arthritis,osteoporosis, obesity and obesity related disorders, (which includeperipheral vascular disease, (including intermittent claudication),cardiac failure and certain cardiac myopathies, myocardial ischaemia,cerebral ischaemia and reperfusion, hyperlipidaemias, atherosclerosis,infertility and polycystic ovary syndrome); the compounds of theinvention may also be useful for muscle weakness, diseases of the skinsuch as acne, various immunomodulatory diseases (such as psoriasis), HIVinfection, inflammatory bowel syndrome and inflammatory bowel diseasesuch as Crohn's disease and ulcerative colitis.

In particular, the compounds of the present invention are of interestfor the prevention, delay or treatment of diabetes mellitus and/orobesity and/or obesity related disorders. In one aspect, the compoundsof the invention are used for prevention, delay or treatment of diabetesmellitus. In another aspect, the compounds of the invention are used forprevention, delay or treatment of obesity. In a further aspect, thecompounds of the invention are used for prevention, delay or treatmentof obesity related disorders.

The inhibition of DGAT1 activity described herein may be applied as asole therapy or in combination with one or more other substances and/ortreatments for the indication being treated. Such conjoint treatment maybe achieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment.Simultaneous treatment may be in a single tablet or in separate tablets.For example such conjoint treatment may be beneficial in the treatmentof metabolic syndrome [defined as abdominal obesity (as measured bywaist circumference against ethnic and gender specific cut-points) plusany two of the following: hypertriglyceridemia (>150 mg/dl; 1.7 mmol/1);low HDLc (<40 mg/dl or <1.03 mmol/1 for men and <50 mg/dl or 1.29 mmol/lfor women) or on treatment for low HDL (high density lipoprotein);hypertension (SBP≧130 mmHg DBP≧85 mmHg) or on treatment forhypertension; and hyperglycemia (fasting plasma glucose≧100 mg/dl or 5.6mmol/l or impaired glucose tolerance or pre-existing diabetesmellitus)—International Diabetes Federation & input from IAS/NCEP].

Such conjoint treatments may include the following main categories:

1) Anti-obesity therapies such as those that cause weight loss byeffects on food intake, nutrient absorption or energy expenditure, suchas orlistat, sibutramine and the like.2) Insulin secretagogues including sulphonylureas (for exampleglibenclamide, glipizide), prandial glucose regulators (for examplerepaglinide, nateglinide);3) Agents that improve incretin action (for example dipeptidyl peptidaseIV inhibitors, and GLP-1 agonists);4) Insulin sensitising agents including PPARgamma agonists (for examplepioglitazone and rosiglitazone), and agents with combined PPARalpha andgamma activity;5) Agents that modulate hepatic glucose balance (for example metformin,fructose 1, 6 bisphosphatase inhibitors, glycogen phopsphorylaseinhibitors, glycogen synthase kinase inhibitors, glucokinaseactivators);6) Agents designed to reduce the absorption of glucose from theintestine (for example acarbose);7) Agents that prevent the reabsorption of glucose by the kidney (SGLTinhibitors);8) Agents designed to treat the complications of prolongedhyperglycaemia (for example aldose reductase inhibitors);9) Anti-dyslipidaemia agents such as, HMG-CoA reductase inhibitors (egstatins); PPAR α-agonists (fibrates, eg gemfibrozil); bile acidsequestrants (cholestyramine); cholesterol absorption inhibitors (plantstanols, synthetic inhibitors); bile acid absorption inhibitors (IBATi)and nicotinic acid and analogues (niacin and slow release formulations);10) Antihypertensive agents such as β-blockers (eg atenolol, inderal);ACE inhibitors (eg lisinopril); Calcium antagonists (eg. nifedipine);Angiotensin receptor antagonists (eg candesartan), α-antagonists anddiuretic agents (eg. furosemide, benzthiazide);11) Haemostasis modulators such as, antithrombotics, activators offibrinolysis and antiplatelet agents; thrombin antagonists; factor Xainhibitors; factor VIIa inhibitors); antiplatelet agents (eg. aspirin,clopidogrel); anticoagulants (heparin and Low molecular weightanalogues, hirudin) and warfarin;12) Agents which antagonise the actions of glucagon; and13) Anti-inflammatory agents, such as non-steroidal anti-inflammatorydrugs (eg. aspirin) and steroidal anti-inflammatory agents (eg.cortisone).

In addition to their use in therapeutic medicine, compounds of formula(I) and their pharmaceutically-acceptable salts are also useful aspharmacological tools in the development and standardisation of in vitroand in vivo test systems for the evaluation of the effects of inhibitorsof DGAT1 activity in laboratory animals such as cats, dogs, rabbits,monkeys, rats and mice, as part of the search for new therapeuticagents.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative, particular andpreferred embodiments of the compounds of the invention described hereinalso apply. The alternative, particular and preferred embodiments of theinvention described herein also apply to a compound of formula (I), or apharmaceutically-acceptable salt, or a pro-drug thereof.

As indicated above, all of the compounds, and their correspondingpharmaceutically-acceptable salts, are useful in inhibiting DGAT1. Theability of the compounds of formula (I), and their correspondingpharmaceutically-acceptable (acid addition) salts, to inhibit DGAT1 maybe demonstrated employing the following enzyme assay:

Human Enzyme Assay

See, for example, International Application WO 2005/044250.

The in vitro assay to identify DGAT1 inhibitors uses human DGAT1expressed in insect cell membranes as the enzyme source (Proc. Natl.Acad. Sci. 1998, 95, 13018-13023). Briefly, sf9 cells were infected withrecombinant baculovirus containing human DGAT1 coding sequences andharvested after 48 h. Cells were lysed by sonication and membranesisolated by centrifuging at 28000 rpm for 1 h at 4° C. on a 41% sucrosegradient. The membrane fraction at the interphase was collected, washed,and stored in liquid nitrogen.

DGAT1 activity was assayed by a modification of the method described byColeman (Methods in Enzymology 1992, 209, 98-102). Compound at 0.0000256μM (or 0.003 μM)-33 μM (final cone.) (typically 10 μM) was incubatedwith 4 μg/ml (final cone) membrane protein, 5 mM MgCl₂, and 100 μM 1,2dioleoyl-sn-glycerol (dissolved in acetone with a final assay conc. ofacetone of 1.8%; other acetone concentrations may be used asappropriate, for example 10%) in a total assay volume of 200 μl in a 96well plate. The reaction was started by adding ¹⁴C oleoyl coenzyme A (30μM final concentration) and incubated at room temperature for 30minutes. The reaction was stopped by adding 200 μl 2-propanol:heptane7:1. Radioactive triolein product was separated into the organic phaseby adding 300 μl heptane and 100 μl 0.1 M carbonate buffer pH 9.5. DGAT1activity was quantified by counting aliquots of the upper heptane layerby liquid scintillography.

Using this assay the compounds generally show activity with an IC₅₀around or below 10 μM, preferably below 10 μM (i.e. IC₅₀<10 μM),preferably <1 μM, more preferably <0.1 μM, particularly, <0.05 μM, andmore particularly <0.01 μM. Stated figures are usually a mean of anumber of measurements (usually 2 measurements) according to standardpractice.

In some cases % inhibition data may have been provided at a particularconcentration (10 μM).

Example 1 showed an IC₅₀=0.016 μM (using an assay acetone concentrationof 1.8%) and 0.079 μM (using an assay acetone concentration of 10%).

Examples 2 to 20 showed respectively IC₅₀=0.071 μM; 0.023 μM; 0.042 μM;0.018 μM; 5.71 μM; 5.09 μM; 0.233 μM; 0.674 μM; 1.34 μM; 0.102 μM; 0.025μM; 0.428 μM; 0.159 μM; 0.157 μM; 1.23 μM; 0.418 μM; 2.85 μM; 1.55 μMand 6.31 μM.

Examples 21 to 54 showed respectively IC₅₀=0.27 μM; 0.067 μM; 0.096 μM;1 μM; 0.1 μM; 1.5 μM; 0.31 μM; 0.038 μM; 0.1 μM; 0.032 μM; 0.17 μM; 0.27μM; 1.3 μM; 3 μM; 0.96 μM; Example 36=46-67% inhibition at 10 μM;Example 37=47-50% inhibition at 10 μM; 2.4 μM; 3 μM; 1.4M; 0.95 μM; 0.21μM; 0.066 μM; 0.093 μM; 0.035 μM; 0.047 μM; 0.056 μM; 4.4 μM; 0.57 μM;0.6 μM; 3.4 μM; 4.6 μM; 4.6 μM; 1.3 μM.

Examples 55 to 64 showed respectively IC₅₀=7 μM; Example 56=15-31%inhibition at 10 μM; 6.7 μM; (Example 58—no data); 0.12 μM; 0.09 μM;0.15 μM; 8 μM; 0.18 μM; 0.67 μM.

Example 65 showed an IC₅₀=7.8 μM and Example 66 an IC₅₀=0.88 μM.

Example 67 showed IC₅₀=0.18 μM; Example 68=25% inhibition at 10 μM.

Examples 69 and 70 showed respectively IC₅₀=0.4 μM and IC₅₀=4.9 μM.

The ability of the compounds of formula (I), and their correspondingpharmaceutically-acceptable (acid) salts, to inhibit DGAT1 may furtherbe demonstrated employing the following whole cell assay.

Measurement of Triglyceride Synthesis in HuTu 80 Cells

HuTu80 cells were cultured to confluency in 6 well plates in minimumessential media containing foetal calf serum. For the experiment, themedium was changed to serum-free medium and the cells pre-incubated withcompound solubilised in DMSO (final concentration 0.1%) for 30 minutes.De novo lipogenesis was measured by the addition of 0.12 mM sodiumoleate plus 1 μCi/mL ¹⁴C-sodium oleate complexed to 0.03 mM BSA to eachwell for a further 2 h. The cells were washed in phosphate bufferedsaline and solubilised in 1% sodium dodecyl sulfate. An aliquot wasremoved for protein determination using a protein estimation kit(Perbio) based on the method of Lowry (J. Biol. Chem., 1951, 193,265-275). The lipids were extracted into the organic phase using aheptane:propan-2-ol:water (80:20:2) mixture followed by aliquots ofwater and heptane according to the method of Coleman (Methods inEnzymology, 1992, 209, 98-104). The organic phase was collected and thesolvent evaporated under a stream of nitrogen. The extracts solubilisedin iso-hexane:acetic acid (99:1) and lipids separated via normal phasehigh performance liquid chromatography (HPLC) using a Lichrospherdiol-5, 4×250 mm column and a gradient solvent system ofiso-hexane:acetic acid (99:1) and iso-hexane:propan-2-ol:acetic acid(85:15:1), flow rate of 1 mL/minute according to the method ofSilversand and Haux (1997). Incorporation of radiolabel into thetriglyceride fraction was analysed using a Radiomatic Flo-one Detector(Packard) connected to the HPLC machine

EXAMPLES

The following examples are for illustration purposes and are notintended to limit the scope of this application. Each exemplifiedcompound represents a particular and independent aspect of theinvention. In the following non-limiting Examples, unless otherwisestated:

(i) evaporations were carried out by rotary evaporation under reducedpressure and work-up procedures were carried out after removal ofresidual solids such as drying agents by filtration;(ii) operations were carried out at room temperature, that is in therange 18-25° C. and generally under an atmosphere of an inert gas suchas argon or nitrogen;(iii) yields are given for illustration only and are not necessarily themaximum attainable;(iv) the structures of the end-products of the Formula (I) wereconfirmed by nuclear (generally proton) magnetic resonance (NMR) andmass spectral techniques; proton magnetic resonance chemical shiftvalues were measured on the delta scale and peak multiplicities areshown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br,broad; q, quartet, quin, quintet;(v) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), infra-red (IR) or NMR analysis;(vi) flash chromatography was carried out on silica unless otherwisestated with flash chromatography purifications run on Biotage SP1 or SP4instruments using Biotage Silica columns;(vii) mass spectra were recorded on a Finnigan LCQ Duo ion trap massspectrometer equipped with an electrospray interface (LC-MS) or LC-MSsystem consisting of a Waters ZQ using a LC-Agilent 1100 LC system;(viii) ¹H NMR measurements were performed on a Varian Mercury VXR 300and 400 spectrometer, operating at a 1H frequency of 300 and 400 andVarian UNITY plus 400, 500 and 600 spectrometers, operating at 1Hfrequencies of 400, 500 and 600 respectively. Chemical shifts are givenin ppm with the solvent as internal standard. Protons on heteroatomssuch as NH and OH protons are only reported when detected in NMR and cantherefore be missing.(ix) HPLC separations were performed on a Waters YMC-ODS AQS-3 120Angstrom 3×500 mm or on a Waters Delta Prep Systems using Kromasil C8,10 μm columns. Acidic HPLC was carried out using gradients ofmobilephase A: 100% ACN and mobilephase B: 5% ACN+95% H₂O+0.2% FA.Neutral HPLC was carried out using gradients of mobilephase A: 100% ACNand mobilephase B: 5% ACN+95% 0.1 M NH₄OAc.(x) Reactions performed in a microwave oven were run in a BiotageInitiator Instrument.(xi) A number of chemical nomenclature software packages, such asACDName; ACDLabs Name: Release 9:00, product version 9.04 andStruc=Name/CambridgeSoft ELN, have been used in the naming of compounds.

List of abbreviations herein: ACN Acetonitrile aq Aqueous Boctert-butyloxycarbonyl Brine Saturated solution of sodium chloride inwater BSA Bovine Serum Albumine DCE 1,2-dichloroethane DCMDichloromethane DEE Diethylether DIPEA N,N-Diisopropylethylamine DMAPDimethylaminopyridine DMF N,N-dimethylformamide DMSO DimethylsulphoxideDppf 1,1′-bis(Diphenylphosphino)ferrocene EDCI1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride EDTAEthylenediaminetetraacetic acid EtOAc Ethyl acetate EtOH Ethanol FAFormic acid HOAc Acetic acid HPLC High-performance liquid chromatographyHWE Horner-Wadsworth-Emmons Hz Hertz IPA Isopropylalcohol iPr isopropylLC Liquid chromatography m-CPBA meta-chloroperoxybenzoicacid MeOHMethanol MHz Megahertz mL Millilitre MS Mass spectra NMMN-methylmorpholine NMP N-methylpiperazine NMR Nuclear magnetic resonanceOAc acetate Ph Phenyl PyBOPBenzotriazol-1-yl-oxytri-pyrrolidinophosphonium hexafluorophosphatePyBROP Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate RT Roomtemperature sat saturated TEA Triethylamine Tf trifluoromethylsulfonylTFA Trifluoroacetic acid THF Tetrahydrofurane TLC Thin layerchromatography Ts p-toluenesulfonyl

Example 1{trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid

To a solution of Intermediate 1-1 (363 mg, 0.86 mmol) in DCM (30 mL) wasadded TFA (3 mL) dropwise. The colorless solution gradually turned intopale yellow clear solution. The reaction mixture was stirred under N₂ atRT overnight. The solvent was evaporated to give the title compound(100%).

¹H NMR (600 MHz, CD₃OD) δ 1.22 (q, 2H), 1.59 (q, 2H), 1.85 (s, 1H), 1.94(d, 4H), 2.23 (d, 2H), 2.58 (t, 1H), 2.62 (s, 3H), 2.84 (s, 3H), 7.37(d, 2H), 7.58 (d, 2H); m/z 368 (M+H)⁺.

Intermediate 1-1tert-Butyl{trans-4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}acetate

To a solution of PyBOP (717 mg, 1.38 mmol) and NH₄Cl (196.6 mg, 3.68mmol) in DMF (50 mL) was added Intermediate 1-2 (390.0 mg, 0.92 mmol)and finally DIPEA (0.80 mL, 4.59 mmol) to initiate the reaction. Thesolution was stirred for 5 h at RT. The reaction was quenched by theaddition of sat Na₂CO₃ and extracted with toluene (3×100 mL). Thecombined organics were washed with brine and water, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude material waspurified by flash chromatography using EtOAc (20-60%) in petroleumether. Evaporation of pure product fractions gave title compound (376mg, 96%) as white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.20 (q, 2H), 1.47 (s, 9H), 1.50-1.64 (m, 2H),1.80-2.00 (m, 5H), 2.17 (d, 2H), 2.56 (t, 1H), 2.67 (t, 3H), 2.98 (t,3H), 5.43 (s, 1H), 7.33 (d, 2H), 7.52 (d, 2H), 7.81 (d, 2H); m/z 424(M+H)⁺.

Intermediate 1-26-{4-[trans-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxylicacid

To a solution of Intermediate 1-3 (0.530 g, 1.17 mmol) in THF (10 mL)was added LiOH (1M, 15 mL). The reaction was stirred at room temperaturefor 5 h. THF was removed under vacuum and the aqueous residue wasacidified with 1M HCl and extracted with EtOAc. The organic layer wasdried through a phase separator and concentrated to give the titlecompound (0.5 g, 100%).

¹H NMR (500 MHz, CDCl₃) δ 1.12-1.21 (m, 2H), 1.45 (s, 9H), 1.49-1.57 (m,2H), 1.79-1.96 (m, 5H), 2.15 (d, 2H), 2.51-2.57 (m, 1H), 2.70 (s, 3H),2.97 (s, 3H), 7.33 (d, 2H), 7.48 (d, 2H); m/z 425 (M+H)⁺.

Intermediate 1-3 Ethyl6-{4-[trans-4-(2-tert-butoxy-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxylate

To a solution of Intermediate 1-4 (0.580 g, 2.70 mmol) in DME (22 mL),EtOH (12 mL) and water (5 mL) was added Intermediate D (see afterIntermediate 1-7; 1.244 g, 3.11 mmol), potassium phosphate, tribasic(0.688 g, 3.24 mmol) and PdCl₂(dppf) (0.119 g, 0.16 mmol). The solutionsdegassed with nitrogen for 10 min and then heated in the microwave ovenat 140° C. for 20 min. Additional amounts of Intermediate D andPdCl₂(dppf) was added to drive the reaction. The microwave heating wascontinued at 140° C. for an additional 30 min.

(The ethyl ester can be hydrolyzed here by prolonging the heating timeand adding 3 extra equivalents of potassium phosphate, to giveIntermediate 1-2.)

The mixtures were combined, filtered through a glass filter funnel andevaporated. The remaining black residue was dissolved in EtOAc, washedwith 0.5M HCl and extracted with 2×EtOAc. The combined organics weredried through a phase separator and concentrated. The crude was purifiedby flash chromatography using EtOAc (0-50%) in heptane as eluent.Evaporation gave title compound (1.063 g, 80%) as oil.

¹H NMR (500 MHz, CDCl₃) δ 1.13-1.22 (m, 2H), 1.42 (t, 3H), 1.47 (s, 9H),1.49-1.58 (m, 2H), 1.80-1.95 (m, 5H), 2.16 (d, 2H), 2.49-2.56 (m, 1H),2.66 (s, 3H), 2.81 (s, 3H), 4.45 (q, 2H), 7.30 (d, 2H), 7.53 (d, 2H);m/z 453 (M+H)⁺.

Intermediate 1-4 Ethyl 6-chloro-3,5-dimethylpyrazine-2-carboxylate

To a suspension of Intermediate 1-5 (0.23 g, 1.17 mmol) in butyronitrile(4 mL) was added POCl₃ (0.27 mL, 2.93 mmol). The reaction was heated to150° C. for 10 min in the microwave oven and cooled to RT. To thereaction mixture was added water (2 mL) and the phases were separated.The organic layer was concentrated under reduced pressure. The crudeproduct was purified by flash chromatography using 0.5% HOAc in DCM aseluent to afford the title compound (0.18 g, 73%).

¹H NMR (500 MHz, CDCl₃) δ 1.43 (t, 3H), 2.68 (s, 3H), 2.78 (s, 3H), 4.46(q, 2H); m/z 215 (M+H)⁺.

Intermediate 1-5 Ethyl3,5-dimethyl-6-oxo-1,6-dihydropyrazine-2-carboxylate

To a solution of Intermediate 1-6 (800 mg, 2.53 mmol) in dry DCE (40 mL)was added TFA (1.95 mL, 25.3 mmol). The reaction mixture was heated toreflux for 4 h. The solvent was evaporated and the crude product waspurified by flash chromatography using EtOAc (20-80%) in heptane aseluent. Concentration of pure fractions gave title compound (160 mg,32%) as white-yellow powder. The crude from this reaction can optionallybe used directly in the next step without purification.

¹H NMR (400 Mhz, CDCl₃) δ 4.42 (q, 2H), 2.61 (s, 3H), 2.52 (s, 3H), 1.41(t, 3H); m/z 197 (M+H)⁺.

Intermediate 1-6 Ethyl2-{[N-(tert-butoxycarbonyl)-L-alanyl]amino}-3-oxobutanoate

Intermediate 1-7 (500 mg, 3.2 mmol) and BOC-Ala-NH₂ (843.8 mg, 4.5 mmol,CAS 85642-13-3) were added to a round bottomed flask, sealed andbackfilled with argon. Dry toluene (30 mL) was added via syringe and theresulting heterogeneous mixture was stirred at 90° C. for 10 min to geta homogeneous solution. Meanwhile, the rhodium (II) octanoate dimer(62.3 mg, 0.080 mmol, CAS 73482-96-9) was dissolved in toluene (5 mL)and put on an ultrasound bath for 5 min, to get a fine Rh-dispersion.This dispersion was then added dropwise to the reaction mixture at 80°C. (a violent N₂ effervescence was observed). After stirring another 20min at elevated temperature the reaction mixture was concentrated underreduced pressure to give a black pasty solid. The N—H insertion productcould here be purified or taken directly to the next step. The crude waspurified by flash chromatography using EtOAc (20-80%) in heptane toafford the title compound (850 mg, 84%) (diastercomeric mixture) as ayellow oil. m/z 317 (M+H)⁺.

Intermediate 1-7 Ethyl 2-diazo-3-oxobutanoate

Polymer-bound tosylazide (11 g, 15.4 mmol) (typical loading 1,4 mmol/g,prepared according to Merz et al J. Org. Chem. 2001, 66, 2509-2511) wasswollen in dry DCM (40 mL). Ethyl acetoacetate (1.0 g, 7.7 mmol, CAS141-97-9) and TEA (3.2 mL, 23.1 mmol) were dissolved in DCM (10 mL) andadded to the polymer containing solution. The resulting mixture was thenshaken at RT under nitrogen until the reaction was judged completed byTLC, typically 6 h. The supernatant was filtered off, then the resin waswashed with DCM (3×30 mL) to rinse out residual product. The reactionmixture was then evaporated to dryness to afford the title compound (1.1g, 92%) as yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 4.28 (q, 2H), 2.45 (s, 3H), 1.33 (t, 3H).

Typically these intermediates were not characterized due to theirhigh-energetic properties (Clark et al, Thermochimica Acta, 386, 2002,73-79), but carried through to the next step as crude products.

Preparation of Intermediate D Intermediate Atert-Butyl[4-(4-hydroxyphenyl)cyclohexylidene]acetate

To an ice-cold solution of 4-(4-hydroxy-phenyl)-cyclohexanone (15.22 g,78.4 mmol, CAS 105640-07-1) in THF (375 mL) under N₂ was added NaH inmineral oil (3.28 g, 79.3 mmol) to give a thick suspension.

In a separate flask NaH in mineral oil (4.06 g, 98.0 mmol) was suspendedin dry THF (375 mL) under N₂. The suspension was cooled to 0° C. andtert-butyl P,P-dimethyl phosphonoacetate (16.82 mL, 82.32 mmol, CAS62327-21-3) was added carefully. Both mixtures were stirred for ˜15 minbefore the ice-baths were removed. After 2 h at RT the ketone solutionwas transferred to the ylide solution via syringe. The combined mixturewas stirred under N₂ overnight. The reaction was quenched by theaddition of water (˜100 mL) and THF was then removed under vacuum. Morewater was added (150 mL) and the aqueous solution was extracted withEtOAc (3×200 mL). The combined organic layer was washed with brine(2×200 mL) and dried through a phase separator. Concentration gaveproduct as colorless oil (24.6 g, 99%).

¹H NMR (500 MHz, CDCl₃) δ 1.51 (s, 9H), 1.55-1.65 (m, 2H), 1.97-2.07 (m,3H), 2.29-2.40 (m, 2H), 2.70-2.78 (m, 1H), 3.90-3.96 (m, 1H), 4.60 (s,1H), 5.62 (s, 1H), 6.77 (d, 2H), 7.09 (d, 2H). m/z 287 (M−H)⁻.

Intermediate B tert-Butyl[trans-4-(4-hydroxyphenyl)cyclohexyl]acetate

To a solution of Intermediate A (4.2 g, 14.56 mmol) in EtOAc (120 mL)was added 10% Pd/C (390 mg). The reaction was hydrogenated for 3 h (5Bar). The catalyst was filtered off through Celite and the organicfiltrate was washed with water, dried through a phase separator andconcentrated to a colorless oil (4.02 g of cis:trans mixture). The crudemixture was purified by chiral HPLC (neutral) using a Chiralpak AD(250×50 mm) column and 100% ACN as mobile phase. Purification gave puretrans phenol (2.88 g, 68%) as white solid and also pure cis phenol. NMRanalysis of both isomers confirmed that the wanted (major) isomer wastrans.

¹H NMR (500 MHz, CDCl₃) δ 1.10-1.20 (m, 2H), 1.42-1.52 (m, 2H), 1.48 (s,9H), 1.77-1.92 (m, 5H), 2.17 (d, 2H), 2.38-2.45 (m, 1H), 4.7-4.9 (m,1H), 6.78 (d, 2H), 7.09 (d, 2H); m/z 289 (M−H)⁻.

Intermediate Ctert-Butyl[trans-4-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)cyclohexyl]acetate

To a solution of Intermediate B (2.86 g, 9.85 mmol) in DCM (75 mL) wasadded pyridine (1.59 mL, 19.7 mmol). The solution was cooled on anice-bath and trifluoromethanesulfonic anhydride (1.99 mL, 11.82 mmol,CAS 358-23-6) was added dropwise. The ice-bath was removed and thereaction was stirred for 10 min. The reaction was quenched with 1M HCl,diluted with DCM and washed with saturated NaHCO₃ and brine. The organiclayer was dried through a phase separator and concentrated. The crudeproduct was filtered through silica using 8% EtOAc in heptane as eluent.Concentration of pure product fractions gave title compound (4.06 g,98%) as white crystalline solid.

¹H NMR (500 MHz, CDCl₃) δ 1.12-1.22 (m, 2H), 1.45-1.54 (m, 2H), 1.48 (s,9H), 1.79-1.88 (m, 1H), 1.89-1.95 (m, 4H), 2.17 (d, 2H), 2.48-2.56 (m,1H), 7.20 (d, 2H), 7.28 (d, 2H); m/z 421 (M−H)⁻.

Intermediate Dtert-Butyl{trans-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclohexyl}acetate

To a suspension of PdCl₂(dppf) (0.93 g, 1.27 mmol, CAS 72287-26-4) indioxane (135 mL) under N₂ was added Intermediate C (17.9 g, 42.4 mmol),TEA (17.7 mL, 127 mmol) and finally a 1M solution of4,4,5,5-tetramethyl-1,3,2-dioxaborolane in THF (72 mL, 72 mmol, CAS25015-63-8). The mixture was refluxed for 7 h, cooled to 10° C. andquenched carefully with H₂O. The aqueous solution was extracted with2×DCM and the combined organics were dried through a phase separator andconcentrated to a black oil. Flash chromatography using 6% EtOAc inheptane as eluent gave title compound (12.1 g, 71%) as white powder.

¹H NMR (500 MHz, CDCl₃) δ 1.12-1.22 (m, 2H), 1.36 (s, 12H), 1.49 (s,9H), 1.48-1.61 (m, 2H), 1.80-1.95 (m, 5H), 2.17 (d, 2H), 2.46-2.54 (m,1H), 7.25 (d, 2H), 7.78 (d, 2H). m/z no ionization.

Example 23,5-Dimethyl-6-[4-(trans-4-{2-[(methylsulfonyl)amino]-2-oxoethyl}cyclohexyl)phenyl]pyrazine-2-carboxamide

To a solution of Example 1 (30 mg, 0.082 mmol) in DCM was added DMAP (2mg, 0.02 mmol), TEA (16 μL, 0.122 mmol), EDCl (20 mg, 0.11 mmol) andfinally methanesulfonamide (11 mg, 0.11 mmol, CAS 3144-09-0). Thesolution was stirred at RT overnight. The crude was concentrated andpurified by HPLC (acidic). Evaporation and co-evaporation with toluenegave title compound (22 mg, 60%).

¹H NMR (500 MHz, CDCl₃) δ 1.08-1.18 (m, 2H), 1.45-1.56 (m, 2H),1.76-1.86 (m, 5H), 2.20 (d, 2H), 2.42-2.52 (m, 1H), 2.57 (s, 3H), 2.72(s, 3H), 3.22 (s, 3H), 7.35 (d, 2H), 7.59 (s, 1H), 7.64 (d, 2H), 7.99(s, 1H), 11.67 (s, 1H); m/z 445 (M+H)¹.

Example 36-{4-[trans-4-(2-Amino-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxamide

This compound was synthesised from Example 1 using similar conditions asdescribed in Intermediate 1-1 to afford title compound (40 mg, 38%) aswhite solid.

¹H NMR (500 MHz, DMSO) δ 1.05-1.15 (m, 2H), 1.43-1.53 (m, 2H), 1.69-1.86(m, 5H), 1.97 (d, 2H), 2.47-2.55 (m, 1H), 2.58 (s, 3H), 2.72 (s, 3H),6.71 (s, 1H), 7.24 (s, 1H), 7.35 (d, 2H), 7.59 (s, 1H), 7.64 (d, 2H),7.99 (s, 1H); m/z 367 (M+H)⁺.

Example 4N-({trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}acetyl)-2-methylalanine

This compound was synthesised from Example 1 and alpha-aminoisobutyricacid methyl ester hydrochloride (CAS 15028-41-8) using similarconditions as in Intermediate 1-1. The intermediate methyl ester washydrolysed to the corresponding acid using similar protocol as describedin Intermediate 1-2.

¹H NMR (500 MHz, DMSO) δ 1.04-1.14 (m, 2H), 1.31 (s, 6H), 1.43-1.53 (m,2H), 1.67-1.75 (m, 1H), 1.77-1.85 (m, 4H), 1.96 (d, 2H), 2.48-2.56 (m,1H), 2.57 (s, 3H), 2.72 (s, 3H), 7.35 (d, 2H), 7.59 (hr s, 1H), 7.64 (d,2H), 7.77-7.82 (m, 1H), 8.00 (br s, 1H); m/z 453 (M+H)⁺.

Example 56-{4-[trans-4-(2-Hydroxyethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxamide

To a suspension of Example 1 (50 mg, 0.14 mmol) and NMM (71 μL, 0.64mmol) in THF (1 mL) at 0° C. was added a solution of ethyl chloroformate(61 μL, 0.64 mmol) in THF (0.5 mL). The reaction was stirred at 0° C.for ˜3 h, but additional equivalents of NMM and ethyl chloroformate wereneeded during this time to drive the reaction. The reaction mixture wasadded dropwise to a solution of NaBH₄ in water at 0-5° C. and thecombined mixture was stirred for 30 min. The mixture was partitionedbetween EtOAc and 1M HCl and the organic layer was washed with water,dried through a phase separator and concentrated. The crude wasdissolved in DMSO and purified by HPLC (neutral). Freeze-drying of purefractions gave the title compound (8 mg, 17%) as white powder.

¹H NMR (500 MHz, DMSO) δ 1.02-1.14 (m, 2H), 1.34-1.54 (m, 5H), 1.80-1.87(m, 4H), 2.47-2.57 (m, 1H), 2.58 (s, 3H), 2.73 (s, 3H), 3.43-3.51 (m,2H), 4.30-4.35 (m, 1H), 7.35 (d, 2H), 7.60 (br s, 1H), 7.65 (d, 2H),7.99 (br s, 1H); m/z 354 (M+H)⁺.

Example 6cis-4-{[5-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)pyridin-2-yl]oxy}cyclohexanecarboxylicacid

A solution of Intermediate 6-1 (0.0243 g, 0.06 mmol) in 10 mL of a 4.0 Msolution of HCl in 1.4-dioxane and a few drops of water was stirred at40° C. for 5 h. The solvent was evaporated and the remaining solid waspurified by HPLC (acidic) to afford the title compound (8.7 mg, 42%) asa dry film.

¹H NMR (500 MHz, CD₃OD) δ 1.72-1.83 (m, 4H), 1.90-2.07 (m, 4H), 2.47 (m,1H), 2.67 (s, 3H), 2.85 (s, 3H), 5.27 (s, 1H), 6.92 (d, 1H), 8.03 (dd,1H), 8.45 (s, 1H); m/z 371 (M+H)⁺.

Intermediate 6-1 tert-Butylcis-4-{[5-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)pyridin-2-yl]oxy}cyclohexanecarboxylate

This compound was synthesised from Intermediate 6-2 using similarprocedure as described in Intermediate 1-1. Purification gave titleproduct (24.3 mg, 68%) as white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.45 (s, 9H), 1.67-1.79 (m, 4H), 1.85-2.07 (m,4H), 2.34 (m, 1H), 2.68 (s, 3H), 2.96 (s, 3H), 5.28 (s, 1H), 5.77 (s,1H), 6.84 (d, 1H), 7.76 (s, 1H), 7.82 (dd, 1H), 8.39 (s, 1H); m/z 427(M+H)⁺.

Intermediate 6-26-(6-{[cis-4-(tert-Butoxycarbonyl)cyclohexyl]oxy}pyridin-3-yl)-3,5-dimethylpyrazine-2-carboxylicacid

This compound was synthesised from Intermediate 6-3 and Intermediate 1-4using similar Suzuki conditions as in Intermediate 1-3 to afford thetitle compound (36 mg, 45%) as white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.44 (s, 9H), 1.67-1.79 (m, 4H), 1.84-2.05 (m,4H), 2.34 (m, 1H), 2.72 (s, 3H), 2.97 (s, 3H), 5.27 (s, 1H), 6.85 (d,1H), 7.80 (d, 1H), 8.37 (s, 1H); m/z 428 (M+H)⁺.

Intermediate 6-3 tert-Butylcis-4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}cyclohexanecarboxylate

Intermediate 6-4 (0.124 g, 0.35 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.121 g,0.48 mmol, CAS 73183-34-3) and potassium acetate (0.139 g, 1.41 mmol) in1,4-dioxane (10 mL) was degassed prior to addition of PdCl₂(dppf) (0.013g, 0.02 mmol) under N₂. The reaction was heated at 85° C. for 16 h. Thesolvent was evaporated and the crude was dissolved in EtOAc, washed withwater (2×25 mL), organics dried over Na₂SO₄, filtered and evaporated.The brownish oil was purified by flash chromatography using 5-50% EtOAcin heptane to afford the title compound (74 mg, 52%) as a dry film.

¹H NMR (500 MHz, CDCl₃) δ 1.30 (s, 12H), 1.43 (s, 9H), 1.59-1.77 (m,4H), 1.80-2.00 (m, 4H), 2.29 (m, 1H), 5.25 (m, 1H), 6.67 (d, 1H), 7.88(dd, 1H), 8.48 (d, 1H).

Intermediate 6-4 tert-Butyl cis-4-[(5-bromopyridin-2-yl)oxy]cyclohexanecarboxylate

A solution of Intermediate 6-5 (0.224 g, 0.75 mmol) in1,1-di-tert-butoxy-N,N-dimethylmethaneamine (0.893 mL, 3.72 mmol, CAS36805-97-7) were heated at 120° C. in a microwave oven for 45 min. Thecrude was purified by flash chromatography using EtOAc (5-70%) inheptane to afford the title compound (124 mg, 46%) as white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.43 (s, 9H), 1.58-1.75 (m, 4H), 1.82-2.00 (m,4H), 2.3 (m, 1H), 5.13 (m, 1H), 6.61 (d, 1H), 7.59 (dd, 1H), 8.12 (d,1H); m/z 357 (M+H)⁺.

Intermediate 6-5 cis-4-[(5-Bromopyridin-2-yl)oxy]cyclohexanecarboxylicacid

A solution of (1S,4S)-4-hydroxycyclohexanecarboxylic acid (2.14 g, 14.9mmol) in DMA (10 mL) was added to a stirred suspension of NaH (1.32 g,30.2 mmol) in DMA (15 mL) at 0° C. where it was stirred for 10 min. Thesuspension was taken off the cooling bath and 5-bromo-2-fluoropyridine(1.53 mL, 14.87 mmol, CAS 766-11-0) was added followed by DMA (10 mL).The reaction was heated at 100° C. for 2.5 h. The solvent was evaporatedand DCM and 2M HCl were added, the phases separated and the aqueousphase was extracted with DCM (2×50 mL). The combined organics were driedover MgSO₄, filtered and evaporated. The remaining crude was purified byflash chromatography using 5-75% EtOAc (1% HOAc) in heptane to affordthe title compound (1.86 g, 42%) as solid.

¹H NMR (500 MHz, CDCl₃) δ 1.70 (t, 2H), 1.75-1.86 (m, 2H), 1.90-2.06 (m,4H), 2.49 (m, 1H), 5.18 (m, 1H), 6.64 (d, 1H), 7.62 (dd, 1H), 8.16 (d,1H); m/z 301 (M+H)⁺.

Example 7(cis-4-{[5-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)pyridin-2-yl]oxy}cyclohexyl)aceticacid

This compound was synthesised from Intermediate 7-1 using similarconditions as described in Example 1 to give the title compound (15 mg,42%) as white solid.

¹H NMR (500 MHz, CD₃OD) δ 1.51 (t, 2H), 1.61-1.75 (m, 4H), 1.91 (m, 1H),2.05 (d, 2H), 2.25 (d, 2H), 2.66 (s, 3H), 2.84 (s, 3H), 5.29 (s, 1H),6.91 (d, 1H), 8.02 (dd, 1H), 8.44 (s, 1H); m/z 385 (M+H)⁺.

Intermediate 7-1tert-Butyl(cis-4-{[5-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)pyridin-2-yl]oxy}cyclohexyl)acetate

This compound was synthesised from Intermediate 7-2 using similarconditions as described in Intermediate 1-1 to afford the title compound(42 mg, 66%) as white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.39-1.50 (m, 11H), 1.55-1.69 (m, 4H), 1.87(m, 1H), 2.02-2.06 (m, 2H), 2.16 (d, 2H), 2.66 (s, 3H), 2.93 (s, 3H),5.29 (s, 1H), 6.40 (s, 1H), 6.80 (d, 1H), 7.75-7.82 (m, 2H), 8.37 (d,1H); m/z 441 (M+H)⁺.

Intermediate 7-26-(6-{[cis-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]oxy}pyridin-3-yl)-3,5-dimethylpyrazine-2-carboxylicacid

This compound was synthesised from Intermediate 7-3 and Intermediate 1-4using similar conditions as described in Intermediate 1-3 to afford thetitle compound (64 mg, 44%) as white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.38-1.51 (m, 11H), 1.56-1.69 (m, 4H), 1.88(m, 1H), 2.03 (d, 2H), 2.17 (d, 2H), 2.71 (s, 3H), 2.94 (s, 3H), 5.29(s, 1H), 6.82 (d, 1H), 7.80 (d, 1H), 8.37 (s, 1H), 9.94 (s, 1H); m/z 442(M+H)⁺.

Intermediate 7-3tert-Butyl(cis-4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}cyclohexyl)acetate

This compound was synthesised from Intermediate 7-4 using similarconditions as described in Intermediate 6-3 to afford the title compound(0.149 g, 43%) as white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.43 (s, 12H), 1.39-1.50 (m, 11H), 1.53-1.67(m, 4H), 1.87 (m, 1H), 2.00 (d, 2H), 2.16 (d, 2H), 5.30 (s, 1H), 6.67(d, 1H), 7.89 (dd, 1H), 8.50 (d, 1H).

Intermediate 7-4tert-Butyl{cis-4-[(5-bromopyridin-2-yl)oxy]cyclohexyl}acetate

This compound was synthesised from Intermediate 7-5 using similarconditions as described in Intermediate 6-4 to afford the title compound(0.303 g, 43%) as white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.35-1.46 (m, 11H), 1.52-1.63 (m, 4H), 1.85(m, 1H), 1.96 (d, 2H), 2.14 (d, 2H), 5.16 (s, 1H), 6.59 (d, 1H), 7.58(dd, 1H), 8.13 (d, 1H); m/z 372 (M+H)⁺.

Intermediate 7-5 {cis-4-[(5-Bromopyridin-2-yl)oxy]cyclohexyl}acetic acid

This compound was synthesised from Intermediate 7-6 using similarconditions as described in Intermediate 6-5 to afford the title compound(1.287 g, 68%) as white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.44-1.52 (m, 2H), 1.58-1.68 (m, 4H), 1.93 (m,1H), 2.00 (d, 2H), 2.31 (d, 2H), 5.19 (s, 1H), 6.63 (d, 1H), 7.62 (dd,1H), 8.16 (d, 1H); m/z 316 (M+H)⁺.

Intermediate 7-6 (cis-4-Hydroxycyclohexyl)acetic acid

This compound was synthesised from Intermediate 7-7 using similarconditions as described in Intermediate 1-2 to afford the title compound(0.943 g, 100%) as white solid.

¹H NMR (500 MHz, CD3OD) δ 1.39-1.60 (m, 6H), 1.65-1.73 (m, 2H), 1.83 (m,1H), 2.10 (d, 2H), 3.85 (m, 1H).

Intermediate 7-7 Methyl(cis-4-hydroxycyclohexyl)acetate

A solution of methyl 4-hydroxyphenylacetate (10.01 g, 60.2 mmol, CAS14199-15-6), rhodium (5% on Alumina) (0.073 g, 0.71 mmol) in MeOH (30mL) was hydrogenated at 8 bar. The crude was filtered through Celite andconcentrated at reduced pressure. The remaining colorless oil wasdissolved in isohexane and EtOAc and purified by flash chromatographyusing EtOAc (20-50%) in isohexane to afford the title cis compound (4.31g, 42%) as colorless oil. NMR analysis of both trans and cis isomerswere compared to make sure that the right isomer was used in subsequentsteps.

¹H NMR (500 MHz, CDCl₃) δ 1.40-1.48 (m, 2H), 1.48-1.62 (m, 4H),1.66-1.74 (m, 2H), 1.86 (m, 1H), 2.24 (d, 2H), 3.66 (s, 3H), 3.97 (s,1H).

Example 8(trans-4-{4-{4-[6-Carbamoyl-5-(difluoromethyl)-3-methylpyrazin-2-yl]phenyl}cyclohexyl)aceticacid

This compound was synthesised from Intermediate 8-1 using similarconditions as described in Example 1 to give the title compound (3.8 mg,31%).

¹H NMR (500 MHz, CD₃OD) δ 1.17-1.30 (m, 2H), 1.54-1.67 (m, 2H),1.80-2.00 (m, 5H), 2.24 (d, 2H), 2.56-2.65 (m, 1H), 2.74 (s, 3H), 7.42(m, 2H), 7.67 (m, 2H), 7.79 (t, 1H); m/z 404 (M+H)⁺.

Intermediate 8-1tert-Butyl(trans-4-{4-[6-carbamoyl-5-(difluoromethyl)-3-methylpyrazin-2-yl]phenyl}cyclohexyl)acetate

This compound was synthesised from Intermediate 8-2 using similarconditions as described in Intermediate 1-1 to give the title compound(11 mg, 44%).

¹H NMR (500 MHz, CDCl₃) δ 1.14-1.24 (m, 2H), 1.47 (s, 9H), 1.51-1.63 (m,2H), 1.80-2.01 (m, 5H), 2.18 (d, 2H), 2.53-2.62 (m, 1H), 2.81 (s, 3H),5.72 (s, 1H), 7.37 (m, 2H), 7.56 (m, 2H), 7.84 (s, 1H), 7.97 (t, 1H);m/z 460 (M+H)⁺.

Intermediate 8-26-{4-[trans-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]phenyl}-3-(difluoromethyl)-5-methylpyrazine-2-carboxylicacid

This compound was synthesised from Intermediate 8-3 using similarconditions as described in Intermediate 1-3 to give the title compound(25 mg, 44%).

¹H NMR (500 MHz, CDCl₃) δ 1.14-1.25 (m, 2H), 1.47 (s, 9H), 1.51-1.61 (m,2H), 1.80-2.01 (m, 5H), 2.14-2.21 (m, 2H), 2.53-2.63 (m, 1H), 2.86 (s,3H), 7.35-7.60 (m, 4H), 7.83 (t, 1H); m/z 461 (M+H)⁺.

Intermediate 8-3 Ethyl6-bromo-3-(difluoromethyl)-5-methylpyrazine-2-carboxylate

This compound was synthesised from Intermediate 8-4 using similarprocedure as described in Intermediate 9-3 to afford the title compound(36 mg, 37%).

¹H NMR (500 MHz, CDCl₃) δ 1.45 (t, 3H), 2.83 (s, 3H), 4.50 (q, 2H), 7.24(t, J=55 Hz, 1H); m/z 295 (M+H)⁺.

Intermediate 8-4 Ethyl3-(difluoromethyl)-5-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate

This compound was synthesised from Intermediate 8-5 using similarprocedure as described in Intermediate 1-5. The cyclized intermediateproduct was oxidized by heating at 120° C. for 20 min in a microwaveoven with Pd/C in HOAc to afford the title compound (280 mg, 38.6%).

¹H NMR (500 MHz, CDCl₃) δ 1.46 (t, 3H), 2.59 (s, 3H), 4.51 (q, 2H), 7.36(t, 1H, J=56 Hz); m/z 233 (M+H)⁺.

Intermediate 8-5 Ethyl2-{[N-(tert-butoxycarbonyl)-L-alanyl]amino}-4,4-difluoro-3-oxobutanoate

This compound was synthesised from Intermediate 8-6 using similarprocedure as described in Intermediate 1-6. The crude was used directlyin next step.

Intermediate 8-6 Ethyl 2-diazo-4,4-difluoro-3-oxobutanoate

This compound was synthesised from 4,4-difluoro-3-oxo-butyric acid ethylester (CAS 352-24-9) and polymer-bound tosylazide using similarconditions as described in Intermediate 1-7. The crude was used directlyin next step.

¹H NMR (400 MHz, CDCl₃) δ 1.35 (t, 3H), 4.35 (q, 2H), 6.59 (t, J=56 Hz,1H).

Example 9{trans-4-[4-(6-Carbamoyl-3-ethyl-5-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid

This compound was synthesised from Intermediate 9-1 using similarconditions as described in Example 1 to afford the title compound (5 mg,29%) as white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.17 (q, 2H), 1.21 (t, 3H), 1.52 (q, 2H),1.75-1.88 (m, 1H), 1.92 (d, 4H), 2.22 (d, 2H), 2.52 (t, 1H), 2.88 (q,2H), 2.9 (s, 3H), 6.12 (br s, 1H), 7.28 (d, 2H), 7.42 (d, 2H), 7.80 (brs, 1H); m/z 382 (M+H)⁺.

Intermediate 9-1 tert-Butyl{trans-4-[4-(6-carbamoyl-3-ethyl-5-methylpyrazin-2-yl)phenyl]cyclohexyl}acetate

This compound was synthesised from Intermediate 9-2 using similarconditions as described in Intermediate 1-1 to afford the title compound(20 mg, 30%) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.18 (q, 2H),1.26 (t, 3H), 1.46 (s, 9H), 1.48-1.62 (m, 2H), 1.78-1.87 (m, 1H), 1.94(t, 4H), 2.16 (d, 2H), 2.55 (t, 1H), 2.93 (q, 2H), 2.98 (s, 3H), 5.65(br s, 1H), 7.31 (d, 2H), 7.46 (d, 2H), 7.80 (s, 1H); m/z 438 (M+H)⁺.

Intermediate 9-26-{4-[trans-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]phenyl}-5-ethyl-3-methylpyrazine-2-carboxylicacid

This compound was synthesised from Intermediate 9-3 and Intermediate Dusing similar Suzuki conditions as described in Intermediate 1-2 toafford the title compound (65.7 mg, 67% yield) as white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.14-1.23 (m, 2H), 1.28 (t, 3H), 1.47 (s, 9H),1.55 (q, 2H), 1.78-1.98 (m, 6H), 2.17 (d, 2H), 2.55 (t, 1H), 2.93-3.01(m, 5H), 7.29-7.36 (m, 2H), 7.40-7.47 (m, 2H); m/z 439 (M+H)⁺.

Intermediate 9-3 Ethyl 6-bromo-5-ethyl-3-methylpyrazine-2-carboxylate

To a solution of POBr₃ (0.307 mL, 3.02 mmol, CAS 7789-59-5) in DCE (10mL) was added Intermediate 9-4 (0.160 g, 0.76 mmol). The mixture washeated at 100° C. for 19 h. The reaction was cooled to RT. SaturatedNaHCO₃ was added carefully and the mixture was extracted with DCM. Theextracts were combined, dried over Na₂SO₄, filtered and concentrated.The remaining crude was purified by flash chromatography using EtOAc(0-25%) in heptane to afford the title compound (60.4 mg, 29%) as paleyellow solid.

¹H NMR (500 MHz, CDCl₃) δ 1.30 (t, 3H), 1.41 (t, 3H), 2.74 (s, 3H), 2.98(q, 2H), 4.43 (q, 2H).

Intermediate 9-4 Ethyl5-ethyl-3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate

This compound was synthesised from Intermediate 9-5 using similarconditions as described in Intermediate 1-5 to afford the title compound(160 mg, 21%) as white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.23 (t, 3H), 1.39 (t, 3H), 2.61 (s, 3H), 2.85(q, 2H), 4.40 (q, 2H).

Intermediate 9-5 Ethyl2-({(2S)-2-[(tert-butoxycarbonyl)amino]butanoyl}amino)-3-oxobutanoate

This compound was synthesised from Intermediate 9-6 and Intermediate 1-7using similar conditions as in Intermediate 1-6. Crude residue was takendirectly to next step.

Intermediate 9-6 tert-Butyl[(1S)-1-carbamoylpropyl]carbamate

To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]butanoic acid (1.01g, 4.99 mmol) in DMF (5 mL) at −20° C. was added NMM (1.10 mL, 9.99mmol) and isobutyl chloroformate (1.30 mL, 9.99 mmol). The reaction wasstirred for 10 min at −20° C. The precipitate was removed by filtration.26% NH₄OH (aq) solution (0.39 mL, 9.99 mmol) was added and the reactionwas stirred at −20° C. for 3 h. The volume was reduced under vacuum andhexane was added. A white precipitate was formed after a few minutes.The precipitate was collected in a filter and washed with additionalhexane. The precipitate was recrystallised from EtOAc and hexane to givethe title compound (0.811 g, 80%) as white solid.

¹H NMR (500 MHz, CD₃OD) δ 0.96 (t, 3H), 1.45 (s, 9H), 1.61 (m, 1H), 1.78(m, 1H), 3.93 (t, 1H), 6.63 (s, 1H), 6.96 (s, 1H), 7.51 (s, 1H).

Example 10{trans-4-[4-(6-Carbamoyl-5-ethyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid

This compound was synthesised from Intermediate 10-1 using similarconditions as described in Example 1 to give title compound (13 mg,95%).

¹H NMR (500 MHz, CDCl₃) δ 1.19-1.30 (2H, m), 1.36 (3H, t), 1.52-1.65(2H, m), 1.84-2.04 (5H, m), 2.35 (2H, d), 2.54-2.64 (1H, m), 2.73 (3H,s), 3.39 (2H, q), 7.29 (1H, s), 7.36 (2H, m), 7.52 (2H, m), 8.10 (1H,s), 8.50 (1H, br s); m/z 382 (M+H)⁺.

Intermediate 10-1 tert-Butyl{trans-4-[4-(6-carbamoyl-5-ethyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}acetate

This compound was synthesised from Intermediate 10-2 using similarprocedure as described in Intermediate 1-1 to give title compound (15mg, 50%).

¹H NMR (500 MHz, CDCl₃) δ 1.13-1.25 (m, 2H), 1.36 (t, 3H), 1.47 (s, 9H),1.52-1.62 (m, 2H), 1.80-2.00 (m, 5H), 2.18 (d, 2H), 2.52-2.60 (m, 1H),2.68 (s, 3H), 3.39 (q, 2H), 5.48 (br s, 1H), 7.33 (d, 2H), 7.52 (d, 2H),7.81 (br s, 1H); m/z 438 (M+H)⁺.

Intermediate 10-26-{4-[trans-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]phenyl}-3-ethyl-5-methylpyrazine-2-carboxylicacid

This compound was synthesised from Intermediate 10-3 and Intermediate Dusing similar Suzuki conditions as described in Intermediate 1-3.Purification gave title product (30 mg, 62%).

¹H NMR (500 MHz, CDCl₃) δ 1.13-1.25 (m, 2H), 1.37 (t, 3H), 1.47 (s, 9H),1.52-1.62 (m, 2H), 1.80-2.00 (m, 5H), 2.18 (d, 2H), 2.53-2.61 (m, 1H),2.74 (s, 3H), 3.42 (q, 2H), 7.36 (d, 2H), 7.51 (d, 2H), 11.21 (br s,1H); m/z 439 (M+H)⁺.

Intermediate 10-3 Ethyl 6-bromo-3-ethyl-5-methylpyrazine-2-carboxylate

This compound was synthesised from Intermediate 10-4 using similarprotocol as described in Intermediate 9-3 to give title compound (30 mg,8%).

¹H NMR (500 MHz, CDCl₃) δ 1.30 (t, 3H), 1.42 (t, 3H), 2.71 (s, 3H), 3.06(q, 2H), 4.45 (q, 2H); m/z 275 (M+H)⁺.

Intermediate 10-4 Ethyl3-ethyl-5-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate

This compound was synthesised from Intermediate 10-5 using similarprotocol as described in Intermediate 1-5. Purification gave titlecompound (0.340 g, 67%) as bright yellow oil.

¹H NMR (500 MHz, CDCl₃) δ 1.23 (t, 3H), 1.43 (t, 3H), 2.54 (s, 3H), 3.02(q, 2H), 4.44 (q, 2H), 9.20 (br s, 1H); m/z 211 (M+H)⁺.

Intermediate 10-5 ethylN-(tert-butoxycarbonyl)-L-alanyl-3-oxonorvalinate

This compound was synthesised from Intermediate 10-6 using similarconditions as described in Intermediate 1-6. Crude product (1 g, 46%)was taken directly to next step. m/z 331 (M+H)⁺.

Intermediate 10-6 Ethyl 2-diazo-3-oxopentanoate

This compound was synthesised from ethyl propionylacetate (CAS4949-44-4) and polymer-bound tosylazide using similar protocol asdescribed in Intermediate 1-7. Crude material (0.9 g, 95%) was takendirectly to next step.

Example 11{trans-4-[4-(6-Carbamoyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid

This compound was synthesised from Intermediate 11-1 using similarconditions as described in Example 1 to give title compound (16 mg,53%).

¹H NMR (500 MHz, CDCl₃) δ 1.15-1.25 (m, 2H), 1.51-1.61 (m, 2H),1.83-2.00 (m, 5H), 2.26 (d, 2H), 2.53-2.61 (m, 1H), 2.71 (s, 3H), 7.34(d, 2H), 7.51 (d, 2H), 9.18 (s, 1H); m/z 354 (M+H)⁺.

Intermediate 11-1 tert-Butyl{trans-4-[4-(6-carbamoyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}acetate

This compound was synthesised from Intermediate 11-2 using similarconditions as described in Intermediate 1-1. The crude was takendirectly to next step. m/z 410 (M+H)⁺.

Intermediate 11-26-{4-[trans-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]phenyl}-5-methylpyrazine-2-carboxylicacid

This compound was synthesised from Intermediate 11-3 and Intermediate Dusing similar Suzuki conditions as described in Intermediate 1-3.Purification gave title compound (410 mg, 66%).

¹H NMR (500 MHz, CDCl₃) δ 1.15-1.26 (m, 2H), 1.48 (s, 9H), 1.52-1.62 (m,2H), 1.81-2.00 (m, 5H), 2.19 (d, 2H), 2.54-2.61 (m, 1H), 2.78 (s, 3H),7.37 (d, 2H), 7.53 (d, 2H), 9.26 (s, 1H); m/z 411 (M+H)⁺.

Intermediate 11-3 Methyl 6-bromo-5-methylpyrazine-2-carboxylate

This compound was synthesised from Intermediate 11-4 using similarconditions as described in Intermediate 9-3 to give the title compound(0.493 mg, 54%).

¹H NMR (500 MHz, CDCl₃) δ 2.78 (s, 3H), 4.02 (s, 3H), 9.10 (s, 1H); m/z233 (M+H)⁺.

Intermediate 11-4 Methyl5-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate

To a solution of intermediate 11-5 (0.98 g, 5.76 mmol) in DCM (180 mL)was added polymer-bound sulfurtrioxide (7.3 g, 3 eq, CAS 26412-87-3).The mixture was stirred at RT for 4 days. The polymer was filtered offand washed with portions of DCM. Concentration of filtrate gave titlecompound (0.8 g, 80%) as yellow solid.

¹H NMR (500 MHz, CDCl₃) δ 2.56 (s, 3H), 4.00 (s, 3H), 7.94 (s, 1H); m/z169 (M+H)⁺.

Intermediate 11-5 Methyl5-methyl-6-oxo-1,4,5,6-tetrahydropyrazine-2-carboxylate

To a solution of Intermediate 11-6 (3.0 g, 8.56 mmol) in EtOH (250 mL)under N₂ was added 10% Pd/C (1.35 g) and ammonium formate (2.43 g, 38.5mmol). The solution was stirred at RT for 90 min. The alcohol wasremoved under vacuum and the black residue was dissolved in EtOAc andfiltered through Celite. Concentration of filtrate gave the titlecompound (1.2 g, 80%). m/z 171 (M+H)⁺.

Intermediate 11-6 EthylN-[(1Z)-2-{[(benzyloxy)carbonyl]amino}-3-methoxy-3-oxoprop-1-en-1-yl]-L-alaninate

A solution of Intermediate 11-7 (0.450 g, 0.78 mmol), L-alanine ethylester hydrochloride (0.179, 1.17 mmol, CAS 1115-59-9) and TEA (0.33 mL,2.33 mmol) in MeOH (10 mL) was stirred at RT overnight. The residue wasconcentrated, dissolved in EtOAc (50 mL) and washed with brine (2×25mL). The organic layer was dried through a phase separator andconcentrated. The crude residue was purified by flash chromatographyusing a gradient of EtOAc (30-50%) in heptane as eluent. Pure productfractions were concentrated to give the title compound (230 mg, 85%) ascolorless oil.

¹H NMR (500 MHz, CDCl₃) δ 1.24-1.33 (m, 6H), 3.70 (s, 3H), 3.94-4.02 (m,1H), 4.22 (q, 2H), 5.16 (s, 2H), 5.75 (br s, 1H), 6.13 (br s, 1H), 7.25(d, 1H), 7.30-7.45 (m, 5H); m/z 351 (M+H)⁺.

Intermediate 11-7 Methyl(2Z)-2-{[(benzyloxy)carbonyl]amino}-3-{[(4-methylphenyl)sulfonyl]oxy}acrylate

To a pre-cooled (−30° C.) solution of DMF:DMSO (1:1, 200 mL) undernitrogen was added TsCl (76.3 g, 0.4 mol) in small portions over 30 min.NOTE: This reaction is highly exotermic and careful temperature controlis essential! The solution was stirred at −10° C. for 10 min, then againtaken to −30° C. A solution of cbz-L-serine methyl ester (20.3 g, 0.08mol, CAS 1676-81-9) in DMF was added dropwise, again with carefultemperature control. After stirring for 10 min at −30° C. triethylamine(110 mL, 0.79 mol) was added and the reaction was slowly taken to 0° C.and kept at this temperature for 2 h. The reaction was quenched byaddition of ice-cold water. The solution was extracted with 3×EtOAc,then the combined organic layer was washed extensively with brine andwater. Drying and evaporation gave product as yellow oil (30 g, 94%).

¹H NMR (500 MHz, CDCl₃) δ 2.47 (s, 3H), 3.77 (s, 3H), 5.11 (s, 2H), 6.01(br s, 1H), 7.32-7.41 (m, 7H), 7.48 (s, 1H), 7.84 (d, 2H); m/z 406(M+H)⁺.

Example 12(trans-4-{4-[6-(Aminocarbonothioyl)-3-methylpyrazin-2-yl]phenyl}cyclohexyl)aceticacid

This compound was synthesised from Intermediate 12-1 using similarprocedure as in Example 1 to afford the title compound (46 mg, 100%).

¹H NMR (400 MHz, CDCl₃) δ 1.20-1.34 (m, 2H), 1.50-1.67 (m, 2H), 1.92 (s,1H), 2.0 (d, 4H), 2.37 (d, 2H), 2.60 (t, 1H), 2.78 (s, 3H), 7.38 (d,2H), 7.53 (d, 2H), 7.83 (s, 1H), 9.18 (s, 1H), 9.67 (s, 1H); m/z 370(M+H)⁺.

Intermediate 12-1tert-Butyl(trans-4-{4-[6-(aminocarbonothioyl)-3-methylpyrazin-2-yl]phenyl}cyclohexyl)acetate

A solution of Example 11 (40 mg, 0.10 mmol) and Lawesson's reagent (39.5mg, 0.10 mmol) in toluene:THF (3:1 mL) was heated at 80° C. overnight.An additional amount (0.5 eq) of Lawesson's reagent was added followedby continued heating for another 1 h. The reaction mixture wasconcentrated and purified by flash chromatography using EtOAc (10-30%)in petroleum ether as eluent to give the title compound (37 mg, 89%) asslightly yellowish powder.

¹H NMR (400 MHz, CDCl₃) δ 1.12-1.25 (m, 3H), 1.45 (s, 9H), 1.50-1.60 (m,1H), 1.83 (s, 1H), 1.93 (t, 4H), 2.15 (d, 2H), 2.54 (t, 1H), 2.70 (s,3H), 7.33 (d, 2H), 7.50 (d, 2H), 7.54 (s, 1H), 9.21 (s, 1H), 9.64 (s,1H); m/z 426 (M+H)⁺.

Example 13 {trans-4-[4-(6-Carbamoylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid

This compound was synthesised from Intermediate 13-1 using similarprocedure as described in Example 1 to afford the title compound (0.5 g,95%).

¹H NMR (500 MHz, DMSO) δ 1.08-1.19 (m, 2H), 1.47-1.57 (m, 2H), 1.71-1.87(m, 5H), 2.15 (d, 2H), 2.52-2.58 (m, 1H), 7.40 (d, 2H), 8.27 (d, 2H),9.06 (s, 1H), 9.40 (s, 1H); m/z 340 (M+H)⁺.

Intermediate 13-1 tert-Butyl{trans-4-[4-(6-carbamoylpyrazin-2-yl)phenyl]cyclohexyl}acetate

This compound was synthesised from Intermediate 13-2 and Intermediate Dusing similar Suzuki conditions as described in Intermediate 1-3. Thisgave the title compound (570 mg, 45%) as light-yellow solid.

¹H NMR (500 MHz, CDCl₃) δ 1.14-1.24 (m, 2H), 1.47 (s, 9H), 1.51-1.61 (m,2H), 1.81-1.98 (m, 5H), 2.18 (d, 2H), 2.53-2.61 (m, 1H), 5.67 (br s,1H), 7.39 (d, 2H), 7.77 (br s, 1H), 7.96 (d, 2H), 9.18 (s, 1H), 9.32 (s,1H); m/z 396 (M+H)⁺.

Intermediate 13-2 6-chloropyrazine-2-carboxamide

A solution of 6-chloro-pyrazine carboxylic acid (2.00 g, 12.62 mmol) inDMF (7 mL) was cooled to −40° C. NMP (2.77 mL, 25.23 mmol) and isobutylchloroformate 3.27 mL, 25.23 mmol) were added. The temperature wasallowed to increase to −20° C. during 20 min and then NH₄OH was added. Aprecipitate was rapidly formed and after 15 min it was filtered off andwashed with water. Crystallization from EtOH gave the title compound(670 mg, 34%) as light-brown needles.

¹H NMR (500 MHz, DMSO) δ 7.93 (br s, 1H), 8.24 (br s, 1H), 8.99 (s, 1H),9.12 (s, 1H).

Example 146-{4-[(trans-4-(2-Amino-2-oxoethyl)cyclohexyl]phenyl}pyrazine-2-carboxamide

This compound was synthesised from Example 13 using similar conditionsas described in Intermediate 1-1. Aqueous work-up gave low yield and isnot recommended here (4 mg, 10%).

¹H NMR (500 MHz, DMSO) δ 1.05-1.17 (m, 2H), 1.45-1.56 (m, 2H), 1.71-1.87(m, 5H), 1.99 (d, 2H), 2.50-2.59 (m, 1H), 6.71 (s, 1H), 7.25 (s, 1H),7.39 (d, 2H), 7.88 (s, 1H), 8.26 (d, 2H), 8.40 (s, 1H), 9.07 (s, 1H),9.39 (s, 1H); m/z 339 (M+H)⁺.

Example 156-{4-[trans-4-(2-Hydroxyethyl)cyclohexyl]phenyl}pyrazine-2-carboxamide

This compound was synthesised from Example 13 using similar conditionsas in Example 5 to afford the title compound (3 mg, 11%) as white solid.

¹H NMR (500 MHz, THF) δ 1.11-1.21 (m, 2H), 1.47 (q, 2H), 1.52-1.63 (m,3H), 1.90-1.98 (m, 4H), 2.55-2.64 (m, 1H), 3.33 (br s, 1H), 3.56-3.63(m, 2H), 7.09 (br s, 1H), 7.40 (d, 2H), 7.95 (br s, 1H), 8.15 (d, 2H),9.18 (s, 1H), 9.26 (s, 1H); m/z 326 (M+H)⁺.

Example 16 MethylN-({trans-4-[4-(6-carbamoylpyrazin-2-yl)phenyl]cyclohexyl}acetyl)-2-methylalaninate

This compound was synthesised from Example 13 and alpha-aminoisobutyricacid methyl ester hydrochloride using similar conditions as inIntermediate 1-1. Purification gave title compound (40 mg, 76%).

¹H NMR (500 MHz, CDCl₃) δ 1.13-1.23 (m, 2H), 1.52-1.62 (m, 2H), 1.58 (s,6H), 1.86-1.98 (m, 5H), 2.11 (d, 2H), 2.52-2.61 (m, 2H), 3.76 (s, 3H),5.71 (br s, 1H), 6.02 (br s, 1H), 7.38 (d, 2H), 7.77 (br s, 1H), 7.96(d, 2H), 9.18 (s, 1H), 9.32 (s, 1H); m/z 439 (M+H)⁺.

Example 17N-({trans-4-[4-(6-Carbamoylpyrazin-2-yl)phenyl]cyclohexyl}acetyl)-2-methylalanine

The methyl ester from Example 16 was hydrolysed to the correspondingacid using similar protocol as described in Intermediate 1-2 to affordthe title compound (21 mg, 72%) as white solid.

¹H NMR (500 MHz, DMSO) δ 1.04-1.14 (m, 2H), 1.31 (s, 6H), 1.43-1.53 (m,2H), 1.69-1.85 (m, 5H), 1.99 (d, 2H), 2.48-2.57 (m, 2H), 7.39 (d, 2H),7.87 (br s, 1H), 7.98 (s, 1H), 8.26 (d, 2H), 8.42 (br s, 1H), 9.06 (s,1H), 9.39 (s, 1H), 12.0 (s, 1H); m/z 425 (M+H)⁺.

Example 183-Carbamoyl-5-{4-[(trans-4-(carboxymethyl)cyclohexyl]phenyl}pyrazin-2-aminiumchloride

To a solution of Intermediate 18-1 (26 mg, 0.06 mmol) in dioxane (5 mL)was added a solution of 4M HCl in dioxane (0.316 mL) in one portion. Aprecipitate formed. Water (1 mL) was added to dissolve the precipitate.The reaction mixture was heated in a microwave oven at 120° C.Evaporation gave title compound (25.8 mg, 100%) as yellow solid.

¹H NMR (400 MHz, DMSO) δ 1.05-1.20 (m, 2H), 1.48 (q, 2H), 1.66-1.87 (m,5H), 2.14 (d, 2H), 2.50 (1H, covered by DMSO), 7.29 (d, 2H), 7.64 (s,1H), 8.01 (d, 2H), 8.23 (s, 1H), 8.77 (s, 1H); m/z 355 (M+H—HCl)⁺.

Intermediate 18-1 tert-Butyl{trans-4-[4-(5-amino-6-carbamoylpyrazin-2-yl)phenyl]cyclohexyl}acetate

This compound was synthesised from Intermediate 18-2 using similarprocedure as described in Intermediate 1-1 to afford the title compound(26 mg, 24%) as white-yellow powder.

¹H NMR (400 MHz, CDCl₃) δ 1.08-1.32 (m, 4H), 1.46 (s, 9H), 1.84 (m, 1H),2.16 (d, 2H), 2.52 (t, 1H), 5.46 (s, 1H), 7.31 (d, 2H), 7.78 (d, 2H),7.83 (s, 1H), 8.63 (s, 1H); m/z 411 (M+H)⁺.

Intermediate 18-23-amino-6-{4-[trans-4-(2-tert-butoxy-2-oxoethyl)cyclohexyl]phenyl}pyrazine-2-carboxylicacid

This compound was synthesised from 3-Amino-6-bromo-pyrazine-2-carboxylicacid methyl ester (CAS 6966-01-4) and Intermediate D using similarSuzuki protocol as described in Intermediate 1-3. Crude was notisolated. m/z 412 (M+H)⁺.

Example 193-Carbamoyl-5-{4-[trans-4-(carboxymethyl)cyclohexyl]phenyl}pyridiniumtrifluoroacetate

This compound was synthesised from Intermediate 19-1 using similarprocedure as described in Example 1. Evaporation yielded the titlecompound (22 mg, 69%) as white powder.

¹H NMR (600 MHz, DMSO) δ 1.12 (2H, q), 1.50 (2H, q), 1.74 (1H, s), 1.82(4H, d), 2.13 (2H, d), 2.51 (1H, t); m/z 339 (M+H-TFA)⁺.

Intermediate 19-1 tert-Butyl{trans-4-[4-(5-carbamoylpyridin-3-yl)phenyl]cyclohexyl}acetate

This compound was synthesised from Intermediate 19-2 using similarreaction conditions as described in Intermediate 1-1. Purification gavetitle compound (40 mg, 37%) as white powder.

¹H NMR (400 MHz, CDCl₁) δ 0.78-1.70 (13H, m), 1.83 (1H, s), 1.91 (4H,t), 2.15 (2H, d), 2.52 (1H, t), 5.68 (1H, s), 6.28 (1H, s), 7.33 (2H,d), 7.54 (2H, d), 8.39 (1H, t), 8.95 (1H, s), 8.99 (1H, s); m/z 395(M+H)¹.

Intermediate 19-25-{4-[trans-4-(2-tert-Butoxy-2-oxoethyl)cyclohexyl]phenyl}nicotinic acid

This compound was synthesised from 5-bromonicotinic acid (CAS20826-04-4) and Intermediate D using similar Suzuki protocol asdescribed in Intermediate 1-3. Purification gave title compound (230 mg,74%) as white solid.

¹H NMR (400 MHz, CD₃OD) δ 1.18 (2H, q), 1.44 (9H, s), 1.55 (2H, q), 1.81(1H, s), 1.89 (4H, t), 2, 14 (2H, d), 2.53 (1H, t), 7.34 (2H, d), 7.59(2H, d), 8.50 (1H, t), 8.76 (1H, d), 8.97 (1H, d); m/z 396 (M+H)⁺.

Example 20{trans-4-[4-(6-Carbamoyl-3-methylpyridin-2-yl)phenyl]cyclohexyl}aceticacid

This compound was synthesised from Intermediate 20-1 using similarconditions as described in Example 1 to afford title compound (11 mg,85%).

¹H NMR (400 MHz, CDCl₃) δ 1.02-1.18 (m, 2H), 1.37-1.51 (m, 2H),1.62-1.82 (m, 5H), 2.08 (d, 2H), 2.32 (s, 3H), 2.40-2.51 (m, 1H), 7.27(d, 2H), 7.49 (d, 3H), 7.81 (d, 2H), 7.86 (s, 1H); m/z 353 (M+H)⁺.

Intermediate 20-1 tert-Butyl{trans-4-[4-(6-carbamoyl-3-methylpyridin-2-yl)phenyl]cyclohexyl}acetate

This compound was synthesised from Intermediate 20-2 and Intermediate Dusing similar Suzuki protocol as in Intermediate 1-3. Purification gavetitle product (15 mg, 21%).

¹H NMR (400 MHz, CDCl₃) δ 1.09-1.30 (m, 2H), 1.45 (s, 9H), 1.48-1.61 (m,2H), 1.76-1.98 (m, 5H), 2.15 (d, 2H), 2.41 (s, 3H), 2.48-2.57 (m, 1H),5.60 (s, 1H), 7.29 (d, 2H), 7.45 (d, 2H), 7.71 (d, 1H), 7.87 (s, 1H),8.04 (d, 1H).

Intermediate 20-2 6-chloro-5-methylpyridine-2-carboxamide

To a solution of Intermediate 20-3 (112 mg, 0.65 mmol) in DCM (5 mL) wasadded PyBROP (457 mg, 0.98 mmol), NH₄Cl (70 mg, 1.30 mmol) and DIPEA(0.43 mL, 2.61 mmol). The reaction mixture was stirred at RT for 2 h.After dilution with DCM (15 mL) the solution was washed with sat NaHCO₃(2×15 mL) and water (15 mL), dried through a phase separator andevaporated. The crude product was purified by flash chromatography usingEtOAc in heptane as eluent. Pure fractions were evaporated to dryness toafford the title compound (83 mg, 74%).

¹H NMR (400 MHz, DMSO) δ 2.35 (s, 3H), 7.63 (s, 1H), 7.85-7.90 (m, 3H);m/z 171 (M+H)⁺.

Intermediate 20-3 6-Chloro-5-methylpyridine-2-carboxylic acid

This compound was synthesised from the corresponding Me-ester usingsimilar protocol as described in Intermediate 1-2 to give title compound(0.11 g, 80%); m/z 172 (M+H)⁺.

Intermediate 20-4 Methyl 6-chloro-5-methylpyridine-2-carboxylate

A solution of Intermediate 20-5 (1.67 g, 9.99 mmol) in POCl₃ (15 mL) washeated to reflux for 3 h. After cooling to RT the reaction mixture wasadded to an ice-water solution, basified with 1M NaOH (aq) and extractedwith DCM (3×30 mL). Organic layers were combined, passed through a phaseseparator and evaporated. The crude product was purified by flashchromatography using EtOAc (15%) in heptane as eluent. Pure fractionswere evaporated to dryness to afford the title compound (0.73 g, 39%).

¹H NMR (400 MHz, CDCl₃) δ 2.44 (s, 3H), 3.97 (s, 3H), 7.67 (d, 1H), 7.96(d, 1H); m/z 186 (M+H)⁺.

Intermediate 20-5 Methyl 5-methylpyridine-2-carboxylate 1-oxide

To a solution of Intermediate 20-6 (2.11 g, 14.0 mmol) in DCM (40 mL)was added m-CPBA (4.70 g, 21.0 mmol) and the reaction was stirred at RTfor 5 h. Sat Na₂SO₂ (15 mL) was added and the reaction was stirred for 5min. The two phases were separated and the organic phase was washed with1M NaHCO₃, passed through a phase separator and evaporated. The crudeproduct was taken to the next step without further purification. m/z 168(M+H)⁺.

Intermediate 20-6 Methyl 5-methylpyridine-2-carboxylate

To a solution of 2,5-dimethylpyridine (3.00 g, 28.0 mmol, CAS 589-93-5)in pyridine (15 mL) was added selenium dioxide (4.66 g, 42.0 mmol, CAS7446-08-4). The reaction mixture was heated at reflux overnight. Aftercooling to RT a solid was filtered off and washed with water andpyridine (2×5 mL/wash). The filtrate was evaporated and the cruderetaken in methanol (100 mL). Sulphuric acid (1.34 mL, 25.0 mmol) wasadded and the reaction mixture was heated at reflux for 5 h. Aftercooling to RT the reaction mixture was basified with 20% NaOH (aq). Themethanol was evaporated off and water was added (50 mL). This mixturewas extracted with DEE (3×100 mL). The combined organics were dried(Na₂SO₄) and evaporated to afford the title compound (2.11 g, 50%) aslight-brown oil.

¹H NMR (400 MHz, CDCl₃) δ 2.40 (s, 3H), 3.97 (s, 3H), 7.61 (d, 1H), 8.01(d, 1H), 8.54 (s, 1H).

Example 214-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)bicyclo[2.2.2]octane-1-carboxylicacid

Powdered potassium hydroxide (204 mg, 3.63 mmol) was added in oneportion to Intermediate 21-1 (493 mg, 1.21 mmol) in tert-butanol (10 mL)at 40° C. under nitrogen. The resulting suspension was stirred at 45° C.for 5 h, a thick white precipitate suspension slowly formed. Acetic acid(0.346 mL, 6.05 mmol) was added and the resulting solution stirred for aseveral minutes before being partitioned between EtOAc (100 mL) and INcitric acid (50 mL). The suspension was filtered and dried to afford ofdesired product as a white solid (300 mg), the organic phase wasseparated, dried over MgSO₄, filtered and evaporated to afford crudeproduct as a colourless oil which solidified on standing. The filtratewas purified by preparative HPLC (Waters XBridge Prep C18 OBD column,5μ, silica, 50 mm diameter, 150 mm length), using decreasingly polarmixtures of water (containing 0.1% formic acid) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness andcombined with the solid to afford the title compound (376 mg, 82%) as awhite solid.

¹H NMR (400 MHz, DMSO) δ 1.84 (12H, s), 2.58 (3H, s), 2.73 (3H, s), 7.46(2H, d), 7.57 (1H, s), 7.66 (2H, d), 7.98 (1H, s), 12.08 (1H, s); m/z380 (M+H)⁺.

Intermediate 21-1 Ethyl4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)bicyclo[2.2.2]octane-1-carboxylate

A solution of Intermediate 21-2 (525 mg, 1.37 mmol), Intermediate 21-4(254 mg, 1.37 mmol), and tripotassium phosphate (348 mg, 1.64 mmol) inDME (15 mL), EtOH (5 mL) and water (2 mL) were degassed before additionof (1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCMadduct) (56.2 mg, 0.07 mmol). The reaction mixture was heated to 80° C.,under nitrogen, and left to stir at 80° C. for 2 h. The reaction mixturewas allowed to cool to room temperature and then evaporated. The crudeproduct was partitioned between EtOAc (100 mL) and water (50 mL),filtered through celite and the organic phase was separated, washed withsaturated brine (50 mL). The organic layer was dried over MgSO₄,filtered and evaporated to afford crude product. The crude product waspurified by flash silica chromatography, elution gradient 20 to 50%EtOAc in isohexane. Pure fractions were evaporated to dryness to affordthe title compound (493 mg, 89%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 1.18 (3H, t), 1.85 (12H, s), 2.58 (3H, s), 2.73(3H, s), 4.05 (2H, q), 7.46 (2H, d), 7.57 (1H, s), 7.66 (2H, d), 7.97(1H, s); m/z 408 (M+H)⁺.

Intermediate 21-2 Ethyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)bicyclo[2.2.2]octane-1-carboxylate

To a degassed solution of Intermediate 21-3 (1.66 g, 4.32 mmol) in DMSO(30 mL) was added potassium acetate (1.272 g, 12.96 mmol) andbis(pinacolato)diboron (1.207 g, 4.75 mmol), the reaction mixture wasdegassed for a further 20 minutes.(1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCMadduct) (0.212 g, 0.26 mmol) was added and the suspension was degassedand then heated, under nitrogen at 80° C. for 3 h. The reaction mixturewas allowed to cool, poured onto water (125 mL), the suspension wasfiltered and the solid was purified by flash silica chromatography,elution gradient 0 to 20% EtOAc in isohexane. Pure fractions wereevaporated to dryness to afford the title compound (1.080 g, 65.0%) as awhite solid.

¹H NMR (400 MHz, CDCl₃) δ 1.25 (3H, t), 1.33 (12H, s), 1.84-1.93 (12H,m), 4.12 (2H, q), 7.33 (2H, d), 7.75 (2H, d); m/z (EI+) 384 M⁺.

Intermediate 21-3 Ethyl4-(4-iodophenyl)bicyclo[2.2.2]octane-1-carboxylate

[Bis(trifluoroacetoxy)iodo]benzene (3.78 g, 8.78 mmol) and iodine (1.061g, 4.18 mmol) were added to a stirred solution of ethyl4-phenylbicyclo[2.2.2]octane-1-carboxylate (prepared according to theprocedure described in WO 2007/071966) (2.16 g, 8.36 mmol, CAS10207-26-8) in CHCl₃ (50 mL). The resulting solution was stirred atambient temperature for 90 minutes. The reaction mixture was poured intosodium thiosulfate (100 mL), extracted with DCM (2×100 mL), the organiclayer was washed with aqueous sodium thiosulfate (2×80 mL), separated,dried over MgSO₄, filtered and evaporated to afford a yellow oil whichsolidified on standing. The crude product was purified by flash silicachromatography, elution gradient 0 to 20% EtOAc in isohexane. Purefractions were evaporated to dryness to afford the title compound (2.78g, 87%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.24 (3H, t), 1.79-1.84 (6H, m), 1.88-1.93(6H, m), 4.11 (2H, q), 7.05 (2H, d), 7.61 (2H, d); m/z 385 (M+H)⁺.

Intermediate 21-4 6-Chloro-3,5-dimethylpyrazine-2-carboxamide

Intermediate 1-4 (227 g, 1057.54 mmol) was stirred in ammonia (7N inMeOH) (1957 mL, 89633.59 mmol) at ambient temperature overnight. Themixture was evaporated to dryness and the residue was triturated withether and the suspension was filtered and at 40° C. under vacuum toafford the title compound (181 g, 92%) as a light brown solid.

¹H NMR (400 MHz, DMSO) δ 2.59 (3H, s), 2.67 (3H, s), 7.70 (1H, s), 7.99(1H, s) m/z 186 (M+H)⁺.

Example 222-(4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)bicyclo-[2.2.2]octan-1-yl)aceticacid

This compound was synthesised from Intermediate 22-1 using similarconditions as described in Example 21 to give the title compound (292mg, 77%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 1.60-1.65 (6H, m), 1.80-1.84 (6H, m), 2.05 (2H,s), 2.58 (3H, s), 2.72 (3H, s), 7.45 (2H, d), 7.56 (1H, s), 7.64 (2H,d), 7.97 (1H, s), 11.91 (1H, s); m/z 394 (M+H)⁺.

Intermediate 22-1 Methyl2-(4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)bicyclo[2.2.2]octan-1-yl)acetate

This compound was synthesised from Intermediate 21-4 and Intermediate22-2 using similar conditions as described in Intermediate 21-1 to givethe title compound (392 mg, 96%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 1.57-1.63 (6H, m), 1.80-1.86 (6H, m), 2.15 (2H,s), 2.58 (3H, s), 2.73 (3H, s), 3.58 (3H, s), 7.44 (2H, d), 7.57 (1H,s), 7.64 (2H, d), 7.97 (1H, s); m/z 408 (M+H)⁺.

Intermediate 22-2 Methyl2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)bicyclo[2.2.2]octan-1-yl)acetate

This compound was synthesised from Intermediate 22-3 using similarconditions as described in Intermediate 21-2 to give the title compound(0.701 g, 55.6%) as a white solid.

¹H NMR (400, CDCl₃) δ 1.33 (12H, s), 1.62-1.66 (6H, m), 1.82-1.87 (6H,m), 2.16 (2H, s), 3.65 (3H, s), 7.32 (2H, d), 7.74 (2H, d); m/z (EI+)384 M⁺.

Intermediate 22-3 Methyl2-(4-(4-iodophenyl)bicyclo[2.2.2]octan-1-yl)acetate

This compound was synthesised from methyl2-(4-phenylbicyclo[2.2.2]octan-1-yl)acetate (prepared according to theprocedure described in WO 2007/071966, CAS 70631-58-2) using similarconditions as described in Intermediate 21-3 to give the title compound(1.320 g, 80%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.62-1.66 (6H, m), 1.77-1.82 (6H, m), 2.16(2H, s), 3.66 (3H, s), 7.05 (2H, d), 7.59 (2H, d); m/z (EI+) 384 M⁺.

Example 233-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]adamantane-1-carboxylicacid

This compound was synthesised from Intermediate 23-1 using similarconditions as described in Example 21. Except after 70 minutes thereaction mixture was allowed to cool and 1N citric acid (15 mL) wasadded, the precipitate was collected by filtration, washed with 1Ncitric acid (10 mL), water (10 mL) and dried under vacuum to afford thetitle compound (360 mg, 90%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 1.69-1.73 (2H, m), 1.84-1.89 (8H, m), 1.96 (2H,s), 2.17-2.19 (2H, m), 2.59 (3H, s), 2.74 (3H, s), 7.50 (2H, d), 7.59(1H, s), 7.68 (2H, d), 7.98 (1H, s), 12.07 (1H, s); m/z 406 (M+H)⁺.

Intermediate 23-1 Methyl3-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]adamantane-1-carboxylate

This compound was synthesised from Intermediate 21-4 and Intermediate23-2 using similar conditions as described in Intermediate 21-1 to givethe title compound (412 mg, 74.3%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 1.70-1.73 (2H, m), 1.85-1.91 (8H, m), 1.98 (2H,s), 2.18-2.20 (2H, m), 2.58 (3H, s), 2.73 (3H, s), 3.60 (3H, s), 7.49(2H, d), 7.58 (1H, s), 7.68 (2H, d), 7.97 (1H, s); m/z 420 (M+H)⁺.

Intermediate 23-2 Methyl3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]adamantane-1-carboxylate

This compound was synthesised from Intermediate 23-3 using similarconditions as described in Intermediate 21-2 to give the title compound(1.758 g, 63.9%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.33 (12H, s), 1.73-1.75 (2H, m), 1.88-1.95(8H, m), 2.05 (2H, s), 2.21-2.25 (2H, m), 3.67 (3H, s), 7.37 (2H, d),7.77 (2H, d); m/z 396 (EI+) M⁺.

Intermediate 23-3 Methyl 3-(4-iodophenyl)adamantane-1-carboxylate

This compound was synthesised from Intermediate 23-4 using similarconditions as described in Intermediate 21-3 to give the title compound(2.75 g, 88%) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.72-1.74 (2H, m), 1.89-1.95 (8H, m), 1.99(2H, s), 2.22-2.24 (2H, m), 3.67 (3H, s), 7.11 (2H, d), 7.63 (2H, d);m/z 396 (EI+) M⁺.

Intermediate 23-4 Methyl 3-phenyladamantane-1-carboxylate

Trimethylsilyldiazomethane 2M solution in hexane (8.15 mL, 16.31 mmol)was added dropwise to a stirred solution of3-phenyl-1-adamantanecarboxylic acid (2.09 g, 8.15 mmol, CAS 37589-22-3)in toluene (20 mL) and methanol (10 mL) over a period of 2 minutes. Theresulting solution was stirred at ambient temperature for 60 minutes.The reaction mixture was evaporated to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness toafford the title compound (2.140 g, 97%) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.73-1.75 (2H, m), 1.90-1.93 (8H, m), 2.04(2H, s), 2.22-2.25 (2H, m), 3.67 (3H, s), 7.17-7.21 (1H, m), 7.30-7.38(4H, m); m/z 270 (EI+) M.

Example 242-[3-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]-1-adamantyl]aceticacid

This compound was synthesised from Intermediate 24-1 using similarconditions as described in Example 21 to give the title compound (126mg, 62.0%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 1.62-1.71 (6H, m), 1.75 (2H, s), 1.81-1.88 (4H,m), 2.07 (2H, s), 2.15 (2H, s), 2.59 (3H, s), 2.73 (3H, s), 7.47 (2H,d), 7.58 (1H, s), 7.67 (2H, d), 7.97 (1H, s), 11.89 (1H, s); m/z 420(M+H)⁺.

Intermediate 24-1 Methyl2-[3-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]-1-adamantyl]acetate

This compound was synthesised from Intermediate 21-4 and Intermediate24-2 using similar conditions as described in Intermediate 21-1 to givethe title compound (210 mg, 48.4%) as a colourless oil which solidifiedon standing.

¹H NMR (400 MHz, DMSO) δ 1.60-1.70 (6H, m), 1.73 (2H, s), 1.81-1.89 (4H,m), 2.14-2.16 (2H, m), 2.16 (2H, s), 2.59 (3H, s), 2.74 (3H, s), 3.57(3H, s), 7.47 (2H, d), 7.58 (1H, s), 7.68 (2H, d), 7.97 (1H, s); m/z 434(M+H)⁺.

Intermediate 24-2 Methyl2-[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-adamantyl]acetate

This compound was synthesised from Intermediate 24-3 using similarconditions as described in Intermediate 21-2 to give the title compound(1.240 g, 76%) as a white solid.

¹H NMR (400 MHz, CDCl₁) δ 1.33 (12H, s), 1.61-1.72 (6H, m), 1.75 (2H,s), 1.82-1.90 (2H, m), 2.17 (2H, s), 2.17-2.20 (4H, m), 3.64 (3H, s),7.36 (2H, d), 7.77 (2H, d); m/z 410 (EI+) M⁺.

Intermediate 24-3 Methyl 2-[3-(4-iodophenyl)-1-adamantyl]acetate

This compound was synthesised from methyl2-(3-phenyl-1-adamantyl)acetate (CAS 175721-57-0, prepared according tothe procedure described in WO 2007/071966 using similar conditions asdescribed in Intermediate 21-3 to give the title compound (1.680 g, 81%)as a yellow oil which solidified on standing.

¹H NMR (400 MHz, CDCl₃) δ 1.62-1.71 (8H, m), 1.78-1.84 (4H, m), 2.16(2H, s), 2.17-2.20 (2H, m), 3.65 (3H, s), 7.09 (2H, d), 7.62 (2H, d);m/z 410 (EI+) M.

Example 253-((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)propanoicacid

This compound was synthesised from Intermediate 25-1 using similarconditions as described in Example 21. Except the crude product waspurified by crystallisation from boiling EtOH (˜10 mL) to afford thetitle compound (180 mg, 65.3%) as a pale red solid.

¹H NMR (400 MHz, DMSO) δ 1.02-1.11 (2H, m), 1.27-1.36 (1H, m), 1.43-1.53(4H, m), 1.81-1.87 (4H, m), 2.25 (2H, t), 2.51-2.55 (1H, m), 2.58 (3H,s), 2.73 (3H, s), 7.35 (2H, d), 7.57 (1H, s), 7.64 (2H, d), 7.97 (1H,s), 11.97 (1H, s); m/z 382 (M+H)⁺.

Intermediate 25-1 Methyl3-(1r,4r)-4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)propanoate

Acetonitrile (4.345 mL) added to 1,1bis(di-tert-butylphosphino)ferrocene palladium dichloride (57.7 mg, 0.10mmol) and stirred at room temperature for 5 min before addition ofpotassium carbonate (540 mg, 3.91 mmol), water (4.35 mL) andIntermediate 25-2 (728 mg, 1.96 mmol). After a further 5 minutesIntermediate 21-4 (364 mg, 1.96 mmol) was added and the reaction mixtureheated to 80° C. for 5 hours. The reaction mixture was partitionedbetween EtOAc (100 mL) and water (50 mL) and the mixture was filteredthrough celite, washing through with EtOAc (50 mL). The organic layerwas dried over MgSO₄, filtered and evaporated to afford crude product.The crude product was purified by flash silica chromatography, elutiongradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated todryness to afford the title compound (286 mg, 37.0%) as a red brownsolid.

¹H NMR (400 MHz, DMSO) δ 1.02-1.13 (3H, m), 1.26-1.37 (1H, m), 1.42-1.53(4H, m), 1.80-1.88 (4H, m), 2.35 (2H, t), 2.58 (3H, s), 2.74 (3H, s),3.59 (3H, s), 7.34 (2H, d), 7.57 (1H, s), 7.64 (2H, d), 7.96 (1H, s);m/z 396 (M+H)⁺.

Intermediate 25-2 Methyl3-(1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)propanoate

A solution of Intermediate 25-3 (4.40 g, 11.16 mmol) in dioxane (85 mL)was degassed with nitrogen for a period of 5 minutes. Potassium acetate(3.28 g, 33.47 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.12 g,12.27 mmol),(1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCMadduct) (0.551 g, 0.67 mmol) and 1,1′-Bis(diphenylphosphino)ferrocene(0.375 g, 0.67 mmol) were added. The resulting mixture was stirred at85° C. under nitrogen for 17 hours. The reaction mixture wasconcentrated and diluted with EtOAc (200 mL), and then mixture wasfiltered through celite. The filtrate was washed with saturated brine,the organic layer was dried over MgSO₄, filtered and evaporated toafford crude product. The crude product was purified by flash silicachromatography, elution gradient 0 to 20% EtOAc in isohexane. Purefractions were evaporated to dryness to afford the title compound (2.68g, 64.5%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.02-1.13 (2H, m), 1.31-1.33 (1H, m), 1.33(12H, s), 1.40-1.52 (2H, m), 1.59 (2H, q), 1.84-1.92 (4H, m), 2.36 (2H,t), 2.43-2.52 (1H, m), 3.68 (3H, s), 7.21 (2H, d), 7.73 (2H, d); m/z 372(EI+) M⁺.

Intermediate 25-3 Methyl3-((1r,4r)-4-(4-(trifluoromethylsulfonyloxy)phenyl)-cyclohexyl)propanoate

Triethylamine (2.59 mL, 18.57 mmol) was added to a stirred solution ofIntermediate 25-4 (3.27 g, 12.46 mmol) and trifluoromethanesulphonicanhydride (2.56 mL, 15.58 mmol) in DCM (120 mL) cooled to 0° C., over aperiod of 5 minutes under nitrogen. The resulting red solution wasstirred at 0° C. for 2 hours and then allowed to warm to ambienttemperature overnight. The reaction mixture was diluted with DCM (100mL), and washed sequentially with water (100 mL), saturated NaHCO₃ (100mL), and saturated brine (100 mL). The organic layer was dried overMgSO₄, filtered and evaporated to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness toafford the title compound (4.42 g, 90%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.07-1.11 (2H, m), 1.29-1.35 (1H, m),1.37-1.47 (2H, m), 1.58 (2H, q), 1.88-1.91 (4H, m), 2.36 (2H, t),2.46-2.53 (1H, m), 3.68 (3H, s), 7.15-7.19 (2H, m), 7.23-7.27 (2H, m);m/z 394 (EI+) M⁺.

Intermediate 25-4 Methyl3-(1r,4r)-4-(4-hydroxyphenyl)cyclohexyl)propanoate

A solution of Intermediate 25-5 (3.82 g, 15.38 mmol) in MeOH (100 mL)and concentrated H₂SO₄ (1.0 mL) was stirred at 70° C. for 3 hours andallowed to cool to ambient temperature overnight. The reaction mixturewas evaporated to dryness and redissolved in EtOAc (200 mL) and washedwith saturated brine (2×150 mL). The organic layer was dried over MgSO₄,filtered and evaporated to afford crude product. The crude product waspurified by flash silica chromatography, elution gradient 0 to 20% EtOAcin isohexane. Pure fractions were evaporated to dryness to afford thetitle compound (3.27 g, 81%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.01-1.12 (2H, m), 1.26-1.33 (1H, m),1.35-1.45 (2H, m), 1.58 (2H, q), 1.83-1.89 (4H, m), 2.36 (2H, t),2.35-2.44 (1H, m), 3.68 (3H, s), 4.62 (1H, s), 6.73-6.77 (2H, m),7.04-7.08 (2H, m); m/z 262 (EI+) M⁺.

Intermediate 25-5 3-(1r,4r)-4-(4-Hydroxyphenyl)cyclohexyl)propanoic acid

A solution of Intermediate 25-6 (5.49 g, 17.86 mmol) and sodiumhydroxide (10.71 g, 267.88 mmol) in 1,2-propanediol (65 mL) and water(16 mL) was heated to 140° C. for 1 hour. The reaction mixture wasallowed to cool to ambient temperature, adjusted to pH 2 with 2M HCl andthe suspension was extracted into EtOAc (2×200 mL). The organic extractswere combined, washed with saturated brine (200 mL), dried over MgSO₄,filtered and evaporated to afford crude product. This was slurried inisohexane (120 mL), filtered and air dried to afford the title compound(3.87 g, 86%) as a white solid, which was used without furtherpurification.

¹H NMR (400 MHz, DMSO) δ 0.95-1.05 (2H, m), 1.16-1.39 (3H, m), 1.44 (2H,q), 1.73-1.79 (4H, m), 2.23 (2H, t), 2.29-2.38 (1H, m), 6.62-6.66 (2H,m), 6.98 (2H, d), 9.03 (1H, s), 11.92 (1H, s); m/z 247 (M−H)⁻.

Intermediate 25-6 4-((1r,4r)-4-(2-Cyanoethyl)cyclohexyl)phenylmethanesulfonate

Sodium cyanide (1.669 g, 34.06 mmol) was added to a stirred solution ofIntermediate 25-7 (8.55 g, 22.71 mmol) in DMF (153 mL). The resultingmixture was stirred at 80° C. for 3 h and then allowed to cool toambient temperature. The reaction mixture was diluted with EtOAc (150mL), and washed with saturated brine (2×250 mL). The organic layer wasdried over MgSO₄, filtered and evaporated to afford desired product.This still contained DMF so it was re dissolved in EtOAc (150 mL), andwashed with saturated brine (2×200 mL), the organic layer was dried overMgSO₄, filtered and evaporated to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient 30to 60% EtOAc in isohexane. Pure fractions were evaporated to dryness toafford the title compound (4.08 g, 58.4%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.06-1.16 (2H, m), 1.41-1.52 (3H, m), 1.54(3H, s), 1.64 (2H, q), 1.89-1.95 (4H, m), 2.40 (2H, t), 2.47-2.53 (1H,m), 3.13 (3H, s), 7.18-7.24 (4H, m); m/z 307 (EI+) M⁺.

Intermediate 25-74-(1r,4r)-4-(2-(Methylsulfonyloxy)ethyl)cyclohexyl)phenylmethanesulfonate

Methanesulphonyl chloride (6.56 mL, 84.58 mmol) was added to a stirredsuspension of Intermediate 25-8 (8.47 g, 38.45 mmol) and triethylamine(11.79 mL, 84.58 mmol) in DCM (300 mL). The resulting solution wasstirred at ambient temperature for 16 h. The reaction mixture was washedwith saturated brine (100 mL), the organic layer was dried over MgSO₄,filtered and evaporated to afford crude product. The crude product waspurified by flash silica chromatography, elution gradient 20 to 70%EtOAc in isohexane. Pure fractions were evaporated to dryness to affordthe title compound (13.84 g, 96%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 0.99-1.15 (2H, m), 1.32-1.51 (3H, m), 1.62 (2H,q), 1.75-1.87 (4H, m), 2.52-2.56 (1H, m), 3.16 (3H, s), 3.27 (3H, 3),4.26 (1H, t), 7.22-7.26 (2H, m), 7.31-7.35 (2H, m); m/z 399 (M+Na)⁺.

Intermediate 25-8 4-((1r,4r)-4-(2-Hydroxyethyl)cyclohexyl)phenol

A 1M solution of lithium aluminum hydride in THF (80 mL, 79.75 mmol) wasadded dropwise to a stirred solution of methyl2-((1r,4r)-4-(4-hydroxyphenyl)cyclohexyl)acetate (prepared according toWO 2004/047755) (12.3 g, 49.53 mmol, CAS 701232-67-9) in THF (280 mL) at0° C. under nitrogen. A thick suspension formed so the mixture wasremoved from the cooling bath and stirred at ambient temperature for 1h. The reaction mixture was cooled in 0° C. and carefully quenched withsaturated NH₄Cl (75 mL), water (50 mL) and 2N HCl (50 mL). The mixturewas filtered through celite, washing through with MeOH (150 mL) andEtOAc (2×250 mL). The filtrate was concentrated, the residue was dilutedwith EtOAc (300 mL), washed sequentially with 2N HCl (100 mL) andsaturated brine (200 mL). The organic layer was dried over MgSO₄,filtered and evaporated to afford the title compound (10.37 g, 95%) as awhite solid.

¹H NMR (400 MHz, DMSO) δ 0.97-1.06 (2H, m), 1.29-1.42 (5H, m), 1.71-1.79(4H, m), 2.29-2.36 (1H, m), 3.42-3.47 (2H, m), 4.27 (1H, t), 6.64 (2H,d), 6.98 (2H, d), 9.03 (1H, s); m/z 220 (EI+) M⁺.

Example 26(1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenoxy)cyclohexanecarboxylicacid

A solution of Intermediate 26-1 (561 mg, 1.22 mmol) in TFA (6.098 mL)allowed to stand at ambient temperature for 30 minutes. The reactionmixture was evaporated and ether was added to the residue to give asolid which was purified by recrystallisation from boiling absolute EtOH(˜10 mL) to afford the title compound (293 mg, 59.5%) as a yellow solid.

¹H NMR (400 MHz, DMSO) δ 1.45-1.59 (4H, m), 1.93-2.00 (2H, m) 2.08-2.10(2H, m), 2.28-2.34 (1H, m), 2.59 (3H, s), 2.73 (3H, s), 4.48-4.52 (1H,m), 7.32 (1H, d), 7.59 (1H, s), 7.63-7.66 (1H, m), 7.86 (1H, d), 8.05(1H, s), 12.10 (1H, s); m/z 404 (M+H)⁺.

Intermediate 26-1 (1r,4r)-tert-Butyl4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenoxy)cyclohexanecarboxylate

This compound was synthesised from Intermediate 26-2 using similarconditions as described in Intermediate 25-1 to give the title compound(561 mg, 71.5%) as a yellow solid.

¹H NMR (400 MHz, DMSO) δ 1.47 (9H, s), 1.54-1.65 (4H, m), 1.96-2.04 (2H,m), 2.12-2.17 (2H, m), 2.32-2.39 (1H, m), 2.66 (3H, s), 2.80 (3H, s),4.53-4.60 (1H, m), 7.39 (1H, d), 7.66 (1H, s), 7.71 (1H, d), 7.92 (1H,s), 8.12 (1H, s); m/z 460 (M+H)⁺.

Intermediate 26-2 (1r,4r)-tert-Butyl4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)cyclohexanecarboxylate

This compound was synthesised from Intermediate 26-3 using similarconditions as described in Intermediate 25-2 to give the title compound(4.23 g, 88%) as a colourless oil which solidified on standing.

¹H NMR (400 MHz, CDCl₃) δ 1.33 (12H, s), 1.45 (9H, s), 1.55-1.62 (4H,m), 2.03-2.08 (2H, m), 2.13-2.19 (2H, m), 2.24-2.31 (1H, m), 4.25-4.31(1H, m), 6.92 (1H, d), 7.61 (1H, d), 7.79 (1H, s); m/z 436 (EI+) M⁺.

Intermediate 26-3 (1r,4r)-tert-Butyl4-(4-bromo-2-chlorophenoxy)cyclohexane-carboxylate

To a solution of Intermediate 26-4 (5.3 g, 26.46 mmol, CAS 931110-79-1),4-bromo-2-chlorophenol (6.59 g, 31.76 mmol) and triphenylphosphine (8.33g, 31.76 mmol) in THF (200 mL) was added diisopropyl azodicarboxylate(5.73 mL, 29.11 mmol). The solution was stirred at room temperature for4 h. The reaction mixture was evaporated. The crude product was purifiedby flash silica chromatography, elution gradient 0 to 20% EtOAc inisohexane. Pure fractions were evaporated to dryness to afford the titlecompound (4.27 g, 41.4%) as a colourless oil.

¹H NMR (400 MHz, DMSO) δ 1.37-1.53 (13H, m), 1.88-2.03 (4H, m),2.23-2.28 (1H, m), 4.35-4.39 (1H, m), 7.19 (1H, d), 7.42-7.44 (1H, m),7.63 (1H, d); HPLC tR=3.65 min.

Intermediate 26-4 (1s,4s)-tert-Butyl 4-hydroxycyclohexanecarboxylate

To a suspension of (1s,4s)-4-hydroxycyclohexanecarboxylic acid (5 g,34.68 mmol, CAS 3685-22-1) in toluene (160 mL) at 90° C. was addedN,N-Dimethylformamide di-tert-butyl acetal (16.63 mL, 69.36 mmol) in oneportion. The resultant solution was stirred at 90° C. for 1 h. A furtherportion of N,N-Dimethylformamide di-tert-butyl acetal (16.63 mL, 69.36mmol) was then added and the reaction mixture stirred for 30 min at 90°C. and then room temperature overnight. Further N,N-Dimethylformamidedi-tert-butyl acetal (10 mL) added dropwise over 10 minutes, thereaction mixture was stirred at 70° C. for 1 h and then allowed to cool.The reaction mixture was washed with 2M NaOH (100 mL), brine (100 mL)and then evaporated to give the title compound (5.30 g, 76%) as an oil.

¹H NMR (400 MHz, DMSO) δ 1.36-1.39 (1H, m), 1.39 (9H, s), 1.41-1.51 (6H,m), 1.70-1.81 (2H, m), 2.19-2.25 (1H, m), 3.62 (1H, m), 4.32 (1H, d).

Example 27 (1s,4s)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenoxy)cyclohexanecarboxylicacid

This compound was synthesised from Intermediate 27-1 using similarconditions as described in Example 21 to give the title compound (182mg, 50.8%) as a white solid, which was crystallised from boilingabsolute EtOH (˜2 mL).

¹H NMR (400 MHz, DMSO) δ 1.67-1.74 (4H, m), 1.76-1.93 (4H, m), 2.35-2.41(1H, m), 2.60 (3H, s), 2.73 (3H, s), 4.77 (1H, brs), 7.28 (1H, d), 7.59(1H, s), 7.65 (1H, dd), 7.87 (1H, d), 8.05 (1H, s), 12.07 (1H, s); m/z404 (M+H)⁺.

Intermediate 27-1 (1s,4s)-Methyl4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenoxy)cyclohexanecarboxylate

This compound was synthesised from Intermediate 27-2 and Intermediate21-4 using similar conditions as described in Intermediate 25-1 to givethe title compound (371 mg, 48.1%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 1.68-1.75 (4H, m), 1.78-1.93 (4H, m), 2.52-2.54(1H, m) 2.60 (3H, s), 2.73 (3H, s), 3.61 (3H, s), 4.76-4.79 (1H, m),7.29 (1H, d), 7.59 (1H, s), 7.65 (1H, dd), 7.87 (1H, d), 8.05 (1H, s);m/z 418 (M+H)⁺.

Intermediate 27-2 (1s,4s)-Methyl4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)cyclohexanecarboxylate

This compound was synthesised from Intermediate 27-3 using similarconditions as described in Intermediate 25-2 to give the title compound(4.73 g, 85%) as a pale yellow oil which solidified on standing.

¹H NMR (400 MHz, CDCl₃) δ 1.33 (12H, s), 1.60-1.68 (2H, m), 1.74-1.81(2H, m), 1.98-2.09 (4H, m), 2.37-2.44 (1H, m), 3.69 (3H, s), 4.57-4.60(1H, m), 6.90 (1H, d), 7.60-7.62 (1H, m), 7.80 (1H, d); m/z 394 (EI+)M⁺.

Intermediate 27-3 (1s,4s)-methyl4-(4-bromo-2-chlorophenoxy)cyclohexane-carboxylate

This compound was synthesised from (1r,4r)-methyl4-hydroxycyclohexanecarboxylate (CAS 6125-57-1) and4-bromo-2-chlorophenol using similar conditions as described inIntermediate 26-3 to give the title compound (4.88 g, 55.5%) as acolourless oil.

¹H NMR (400 MHz, DMSO) δ 1.62-1.86 (8H, m), 3.60 (3H, s), 4.66 (1H, m),7.15 (1H, d), 7.42-7.45 (1H, m), 7.64 (1H, d) one CH obscured; HPLCtR=2.99 min.

Example 286-((1r,4s)-4-((2H-Tetrazol-5-yl)methyl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-5′-yl)-3,5-dimethylpyrazine-2-carboxamide

A solution of Intermediate 21-4 (197 mg, 1.06 mmol), Intermediate 28-1(473 mg, 1.06 mmol) and tripotassium phosphate (449 mg, 2.11 mmol) inDME (10 mL), EtOH (6.25 mL) and water (2.5 mL) was degassed beforeaddition of (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II)(43.5 mg, 0.05 mmol). The reaction mixture was heated to 80° C., undernitrogen, and left to stir overnight for 5 hrs. The reaction mixture wasallowed to cool to room temperature and then evaporated. The residue wasacidfied with 2N HCl (3 mL), diluted with water (20 mL) and extractedinto EtOAc (4×50 mL). The organic extracts were combined, dried overMgSO₄, filtered and evaporated to afford crude product. The crudeproduct was purified by preparative HPLC (Waters XBridge Prep C18 OBDcolumn, 5μ silica, 50 mm diameter, 150 mm length), using decreasinglypolar mixtures of water (containing 0.1% formic acid) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (51.9 mg, 11.76%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 1.23-1.38 (2H, m), 1.58-1.73 (6H, m), 1.86-1.96(1H, m), 2.04 (2H, t), 2.63 (3H, s), 2.79 (3H, s), 2.91 (2H, d), 2.97(2H, t), 7.33 (1H, d), 7.55 (1H, d), 7.60 (1H, s), 7.62 (1H, s), 8.02(1H, s); NH not seen; m/z 418 (M+H)⁺.

Intermediate 28-13-(5-(((1r,4s)-5′-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-yl)methyl)-2H-tetrazol-2-yl)propanenitrile

To a solution of triphenylphosphine (1.453 g, 5.54 mmol) andIntermediate 28-2 (900 mg, 2.13 mmol) in THF (25.400 mL) in an ice bathwas added diisopropyl azodicarboxylate (1.133 mL, 5.75 mmol). Theresulting yellow solution was allowed to stir at 0° C., after 2 minutesazidotrimethylsilane (0.820 mL, 6.18 mmol) was added dropwise. After 17hours at ambient temperature further triphenylphosphine (1.453 g, 5.54mmol), diisopropyl azodicarboxylate (1.133 mL, 5.75 mmol) andazidotrimethylsilane (0.820 mL, 6.18 mmol) were added and the suspensionwas stirred at ambient temperature for a further 24 hours. The reactionmixture was cooled in an ice bath and a solution of Sodium nitrite (162mg, 2.34 mmol) in water (3 mL) was added and after 30 minutes a solutionof ammonium cerium(IV) nitrate (1285 mg, 2.34 mmol) in water (10 mL) wasadded (CAUTION: Gas evolution). The reaction mixture was stirred for afurther 45 minutes. The reaction mixture was poured into water (50 mL)and extracted with DCM (200 mL and 100 mL). The organic extracts werecombined, dried over MgSO₄, filtered and evaporated to afford crudeproduct.

The crude product was purified by flash silica chromatography, elutiongradient 0 to 80% EtOAc in isohexane. Mixed fractions were evaporated todryness to afford the title compound (487 mg, 51.1%) as a cream solid.

¹H NMR (400 MHz, DMSO) δ 1.20-1.38 (14H, m), 1.40-1.50 (2H, m),1.53-1.70 (4H, m), 1.83-1.97 (3H, m), 2.82 (2H, t), 2.89 (2H, d), 3.18(2H, t), 4.69 (2H, t), 7.16 (1H, d), 7.48 (1H, d), 7.49 (1H, s); m/z 448(M+H)⁺.

Intermediate 28-2N-(2-Cyanoethyl)-2-((1r,4s)-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-yl)acetamide

3-Aminopropionitrile (0.215 mL, 2.94 mmol) was added to a stirredsolution of Intermediate 28-3 (725 mg, 1.96 mmol),N-ethyldiisopropylamine (1.023 mL, 5.87 mmol) and PyBROP (1.369 g, 2.94mmol) in DCM (50 mL). The resulting solution was stirred at ambienttemperature for 4 hours. The reaction mixture was evaporated to drynessand redissolved in EtOAc (125 mL), and washed sequentially with 2M HCl(75 mL) and saturated brine (75 mL). The organic layer was dried overMgSO₄, filtered and evaporated to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness toafford the title compound (900 mg, 109%) as a white foam.

¹H NMR (400 MHz, DMSO) δ 1.09-1.20 (2H, m), 1.27 (12H, s), 1.42-1.46(2H, m), 1.53-1.67 (4H, m), 1.72-1.79 (1H, m), 1.90 (2H, t), 2.03 (2H,d), 2.63 (2H, t), 2.81 (2H, t), 3.26-3.29 (2H, m), 7.17 (1H, d), 7.46(1H, d), 7.48 (1H, s), 8.16 (1H, t); m/z 423 (M+H)⁺.

Intermediate 28-32-((1r,4s)-5′-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′-dihydrospiro(cyclohexane-1,1′-indene]-4-yl)aceticacid

TFA (15.90 mL) was added to a stirred solution of Intermediate 29-3 (802mg, 1.88 mmol) in DCM (15.90 mL) at 0° C. The resulting solution wasstirred at 0° C. for 30 minutes, the reaction mixture was evaporated andthe residue was azeotroped with toluene to afford the title compound(676 mg, 97%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.21-1.28 (2H, m), 1.33 (12H, s), 1.56-1.70(4H, m), 1.76-1.82 (2H, m), 1.85-1.93 (1H, m), 1.97 (2H, t), 2.31 (2H,d), 2.87 (2H, t), 7.15 (1H, d), 7.64-7.67 (2H, m); COOH not seen; m/z370 (EI+) M.

Example 29 N:2-((1s,4r)-5′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2′,3′-dihydrospiro(cyclohexane-1,1′-indene]-4-yl)aceticacid

A solution of Intermediate 29-1 (0.748 g, 1.66 mmol) in TFA (8 mL)allowed to stand at room temperature for 0.5 h. The reaction mixture wasevaporated to a solid. The crude product was purified byrecrystallisation twice from MeOH to afford the title compound (0.201 g,30.7%) as an off-white crystalline solid.

¹H NMR (400 MHz, DMSO) δ 1.40-1.56 (4H, m), 1.66-1.80 (4H, m), 1.96 (2H,t), 2.03 (1H, br s), 2.39 (2H, d), 2.58 (3H, s), 2.73 (3H, s), 2.89 (2H,t), 7.46-7.50 (2H, m), 7.54 (1H, s), 7.57 (1H, s), 7.97 (1H, s), 11.99(1H, s); m/z 394 (M+H)⁺.

Intermediate 29-1 N: tent-Butyl 2-((1s,4r)-5′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-yl)acetate

This compound was synthesised from Intermediate 29-2 using similarconditions as described in Intermediate 25-1 to give the title compound(0.748 g, 50.3%) as a solid which was a 2:1 mixture with the otherdiastereoisomer. m/z 450 (M+H)⁺.

Intermediate 29-2 N: tert-Butyl2-((1s,4r)-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-yl)acetateand Intermediate 29-3 tert-Butyl2-((1r,4s)-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-yl)acetate

To a solution of Intermediate 29-4 (5.42 g, 12.77 mmol) in THF (125 mL),under nitrogen, was added 10% (w/w) palladium on carbon (1.4 g). Theatmosphere was replaced with hydrogen and the reaction stirred at roomtemperature overnight. The reaction mixture was filtered and evaporatedto a colourless oil. This was dissolved in methanol (ca. 20 mL) andcooled in a dry ice/acetone bath to produce a white solid. Thesuspension was allowed to warm and then evaporated to give the crudeproduct as a white solid. This was recrystallised by dissolving in DCM(ca. 20 mL) adding methanol (ca. 20 mL) and cooling in a dry ice/acetonebath. The resultant suspension was filtered and the collected soliddried to give Intermediate 29-3 (2.290 g, 42.1%) as a white solid. ¹HNMR (400 MHz, DMSO) δ 1.17-1.21 (2H, m), 1.26 (12H, s), 1.40 (9H, s),1.44-1.67 (7H, m), 1.90 (2H, t), 2.13 (2H, d), 2.81 (2H, t), 7.18 (1H,d), 7.46-7.48 (2H, m).

The mother liquors were evaporated to give Intermediate 29-2 (1.610 g,29.6%) as a solid as a 2:1 mixture with the other diastereoisomer.

Intermediate 29-4 N: tert-Butyl2-(5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-ylidene)acetate

This compound was synthesised from Intermediate 29-5 using similarconditions as described in Intermediate 25-2 to give the title compound(5.42 g, 66.4%) as a solid.

¹H NMR (400 MHz, DMSO) δ 1.28 (12H, t), 1.42 (8H, s), 1.60-1.73 (4H, m),2.04-2.13 (3H, m), 2.26 (1H, d), 2.31-2.36 (1H, m), 2.87 (2H, t), 3.66(1H, d), 5.60 (1H, s), 7.17 (1H, d), 7.45-7.47 (1H, m), 7.50 (1H, s) oneproton obscured; m/z 423 (M−H)⁻.

Intermediate 29-5 N: tert-Butyl2-(5′-bromo-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-ylidene)acetate

To a solution of tert-butyldiethylphosphonoacetate (8.80 mL, 37.47 mmol)in THF (100 mL) was added 60% w/w sodium hydride (1.498 g, 37.47 mmol).The reaction mixture was stirred at room temperature for 30 min. Asolution of 5′-bromo-2′,3′-dihydrospiro[cyclohexane-1,1′-inden]-4-one(prepared according to the procedure described in WO 2004/047755, CAS701232-89-5) (8.716 g, 31.22 mmol) in THF (50 mL) was added and stirringcontinued at room temp for 1 hour. The reaction mixture was quenchedwith saturated brine (150 mL), extracted with EtOAc (2×200 mL), theorganic layer was dried over Na₂SO₄, filtered and evaporated to affordthe crude product as a brown oil (13.66 g). The crude oil was trituratedwith isohexane to give a solid which was collected by filtration anddried under vacuum to give the title compound (4.84 g, 41%) as a beigesolid. A second crop of the title compound (2.42 g, 21%) was obtainedfrom the filtrate.

¹H NMR (400 MHz, DMSO) δ 1.42 (9H, s), 1.59-1.69 (4H, m), 2.05-2.12 (3H,m), 2.24-2.35 (2H, m), 2.88 (2H, t), 3.66 (1H, d), 5.60 (1H, s), 7.14(1H, d), 7.27-7.30 (1H, m), 7.38 (1H, t).

Example 302-((1r,4s)-5′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-yl)aceticacid

A solution of Intermediate 30-1 (1.16 g, 2.58 mmol) in TFA (12 mL) wasallowed to stand at RT for 0.5 h. The reaction mixture was evaporated toa solid. The crude product was purified by recrystallisation from MeOHto afford the title compound (0.648 g, 63.8%) as a white crystallinesolid.

¹H NMR (300 MHz, DMSO) δ 1.14-1.27 (2H, m), 1.51-1.80 (7H, m), 1.98 (2H,t), 2.17 (2H, d), 2.58 (3H, s), 2.73 (3H, s), 2.90 (2H, t), 7.30 (1H,d), 7.50 (1H, d), 7.54 (1H, s), 7.62 (1H, s), 8.01 (1H, s), 12.05 (1H,s); m/z 394 (M+H)⁺.

Intermediate 30-1 tert-Butyl2-((1r,4s)-5′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-yl)acetate

This compound was synthesised from Intermediate 29-3 using similarconditions as described in Intermediate 25-1 to give the title compound(1.260 g, 89%) as a solid.

¹H NMR (400 MHz, DMSO) δ 1.20-1.23 (2H, m), 1.41 (9H, s), 1.51-1.69 (7H,m), 1.97 (2H, t), 2.14 (2H, d), 2.57 (3H, s), 2.73 (3H, s), 2.90 (2H,t), 7.29 (1H, d), 7.47-7.57 (2H, m), 7.53 (1H, s), 7.96 (1H, s); m/z 450(M+H)⁺.

Example 31(1r,4s)-5′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carboxylicacid

4M HCl in dioxane (10 mL, 0.43 mmol) was added to Intermediate 31-1 (188mg, 0.43 mmol) in DCM (5 mL). The resulting solution was stirred for 16hours. The resulting mixture was evaporated to dryness and the residuewas slurried with ether then filtered to afford the title compound (158mg, 96%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO) δ 1.48-1.73 (6H, m), 1.85-1.93 (2H, m), 2.00 (2H,t), 2.28-2.36 (1H, m), 2.58 (3H, s), 2.73 (3H, s), 2.91 (2H, t), 7.29(1H, d), 7.50 (1H, d), 7.56 (3H, d), 7.98 (1H, s); m/z 380 (M+H)⁺.

Intermediate 31-1 (1r 4s)-tert-Butyl5′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2′3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carboxylate

This compound was synthesised from Intermediate 31-2 and Intermediate21-4 using similar conditions as described in Intermediate 25-1 to givethe title compound (188 mg, 32.0%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 1.40 (9H, s), 1.54-1.68 (6H, m), 1.86-1.96(2H, m), 2.02 (2H, t), 2.16-2.28 (1H, m), 2.60 (3H, s), 2.82-2.95 (5H,m), 5.40 (1H, s), 7.15 (1H, d), 7.30 (1H, d), 7.33 (1H, dd), 7.72 (1H,s); m/z 436 (M+H)⁺.

Intermediate 31-2 (1r,4s)-tert-Butyl5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carboxylate

This compound was synthesised from Intermediate 31-3 using similarconditions as described in Intermediate 25-2 to give the title compound(3.13 g, 73.7%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.26 (12H, s), 1.39 (19H, s), 1.50 (2H, d),1.50-1.60 (6H, m), 1.80-1.90 (2H, m), 1.93 (2H, t), 2.15-2.25 (1H, m),2.81 (2H, t), 7.07 (1H, d), 7.59 (1H, dd), 7.59 (1H, s).

Intermediate 31-3 (1r,4s)-tert-Butyl5′-bromo-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carboxylate

To a solution of Intermediate 31-4 (3.47 g, 11.22 mmol) in tert-butanol(100 mL) was added DMAP (0.411 g, 3.37 mmol) and di-tort-butyldicarbonate (14.70 g, 67.34 mmol) (effervescence). The resultingsolution was stirred at ambient temperature for 16 hours. SaturatedNaHCO₃ (100 mL) was added and the reaction stirred for 30 minutes beforeadding EtOAc (400 mL). The organic layer was separated and washed withwater (200 mL) then saturated brine (200 mL) and evaporated to affordcrude product. The crude product was purified by flash silicachromatography, elution gradient 0 to 10% EtOAc in isohexane. Purefractions were evaporated to dryness to afford the title compound (3.76g, 92%) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.46 (9H, s), 1.52-1.67 (6H, m), 1.90-1.97(2H, m), 1.98-2.03 (2H, m), 2.20-2.30 (1H, m), 2.86 (2H, t), 6.96 (1H,d), 7.28 (1H, dt), 7.32 (1H, d).

Intermediate 31-4(1r,4s)-5′-Bromo-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carboxylicacid

Oxone (6.98 g, 11.36 mmol) was added to Intermediate 31-5 (3.33 g, 11.36mmol), in DMF (70 mL). The resulting suspension was stirred for 16hours. The reaction mixture was diluted with EtOAc (300 mL), and washedsequentially with water (3×150 mL) and saturated brine (150 mL). Theorganic layer was evaporated to afford the title compound (3.51 g,100%).

¹H NMR (400 MHz, DMSO) δ 1.30-1.73 (6H, m), 1.80-2.00 (4H, m), 2.20-2.32(1H, m), 2.83 (2H, t), 7.12 (1H, d), 7.31 (1H, dt), 7.36 (1H, t), 12.03(1H, s); m/z 309 M−H⁻.

Intermediate 31-5(1r,4s)-5′-Bromo-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carbaldehydeand Intermediate 31-6(1s,4r)-5′-Bromo-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carbaldehyde

(Methoxymethyl)triphenylphosphonium chloride (20.76 g, 60.55 mmol) wasadded to a stirred suspension of potassium tert-butoxide (6.79 g, 60.55mmol) in 1,4-dioxane (113 mL) at ambient temperature, over a period of10 minutes under nitrogen. The resulting red solution was stirred atambient temperature for 2 hours and then a solution of5′-bromo-2′,3′-dihydrospiro[cyclohexane-1,1′-inden]-4-one (preparedaccording to the procedure described in WO 2004/047755, CAS 701232-89-5)(7.35 g, 26.33 mmol) in 1,4-dioxane (63.4 mL) was added over a period of10 minutes under nitrogen. The resulting solution was stirred at ambienttemperature for 1 hour and then heated at 70° C. for 16 hours. Thereaction mixture was poured into water (200 mL), extracted with EtOAc(2×200 mL), the organic layer was washed with saturated brine (200 mL)and evaporated to afford a black oil. To the crude oil was added EtOAcand isohexane (1:3, 200 mL) to give a solid which was collected byfiltration, washed with EtOAc and isohexane (75 mL). The filtrate wasevaporated to afford a solid residue, which was added to 90% acetic acidin water (200 mL, 3493.64 mmol). The resulting solution was stirred at70° C. for 16 hours, the mixture was allowed to cool, evaporated todryness and the crude product was purified by flash silicachromatography, elution gradient 0 to 15% EtOAc in isohexane. Purefractions were evaporated to dryness to afford Intermediate 31-5 (3.33g, 43.1%) and Intermediate 31-6 (1.17 g, 15%) as colourless gums.

Intermediate 31-5

¹H NMR (400 MHz, CDCl₁) δ 1.36-1.67 (6H, m), 1.84-2.00 (4H, m),2.19-2.29 (1H, m), 2.80 (2H, t), 6.92 (1H, m), 7.22 (1H, m), 7.23 (1H,dd), 9.61 (1H, d); m/z (EI+) 292 M⁺.

Intermediate 31-6

¹H NMR (400 MHz, CDCl₃) δ 1.35-1.60 (4H, m), 1.68-1.80 (2H, m), 1.93(2H, t), 2.09 (2H, dt), 2.37-2.44 (1H, m), 2.75-2.85 (2H, m), 6.90 (1H,d), 7.19 (1H, d), 7.24 (1H, d), 9.72 (1H, s); m/z 292 (EI+) M⁺.

Example 32(1s,4r)-5′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2′3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carboxylicacid

This compound was synthesised from Intermediate 32-1 using similarconditions as described in Example 31 to give the title compound (176mg, 59.9%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO) δ 1.45 (2H, dd), 1.72 (3H, dd), 1.77 (1H, m),1.96 (1H, s), 1.99 (3H, t), 2.58 (4H, s), 2.73 (3H, s), 2.90 (2H, t),7.25 (1H, d), 7.49 (1H, dd), 7.55 (1H, d), 7.57 (1H, s), 7.97 (1H, s);m/z 380 (M+H)⁺.

Intermediate 32-1 (1s,4r)-tert-Butyl5′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carboxylate

This compound was synthesised from Intermediate 32-2 and Intermediate21-4 using similar conditions as described in Intermediate 25-1 to givethe title compound (342 mg, 58.2%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 1.40-1.50 (2H, m), 1.44 (9H, s), 1.65-1.75(2H, m), 1.75-1.85 (2H, m), 1.95-2.08 (4H, m), 2.45-2.51 (1H, m), 2.60(3H, s), 2.85-2.93 (5H, m), 5.39 (1H, s), 7.26-7.35 (3H, m), 7.73 (1H,s); m/z 436 (M+H)⁺.

Intermediate 32-2 (1s,4r)-tert-Butyl5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carboxylate

This compound was synthesised from Intermediate 32-3 using similarconditions as described in Intermediate 25-2 to give the title compound(0.935 g, 62.3%) as a colourless oil which solidified on standing.

¹H NMR (400 MHz, CDCl₃) δ 1.32 (12H, s), 1.44-1.47 (2H, m), 1.50 (9H,s), 1.67-1.86 (4H, m), 1.96 (2H, t), 2.01-2.09 (2H, m), 2.48-2.53 (1H,m), 2.83-2.90 (2H, m), 7.25 (1H, d), 7.63 (1H, d), 7.67 (1H, s); m/z 412(EI+) M⁺.

Intermediate 32-3 (1s,4r)-tert-Butyl5′-bromo-2′3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carboxylate

This compound was synthesised from Intermediate 32-4 using similarconditions as described in Intermediate 31-3 to give the title compound(1.330 g, 89%) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.42-1.46 (2H, m), 1.49 (9H, s), 1.67-1.81(4H, m), 1.96 (2H, t), 2.00-2.06 (2H, m), 2.48-2.53 (1H, m), 2.85 (2H,t), 7.08 (1H, d), 7.26-7.28 (1H, m), 7.32 (1H, s); m/z 364 (EI+) M⁺.

Intermediate 32-4(1s,4r)-5′-Bromo-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carboxylicacid

This compound was synthesised from Intermediate 31-6 using similarconditions as described in Intermediate 31-4 to give the title compound(1.27 g, 100%) as a solid.

¹H NMR (400 MHz, DMSO) δ 1.35-1.44 (2H, m), 1.60-1.73 (4H, m), 1.85-2.00(4H, m), 2.53 (1H, q), 2.82 (2H, t), 7.08 (1H, d), 7.30 (1H, dt), 7.37(1H, t), 12.12 (1H, s); m/z 309 (M−H)⁻.

Example 332-(1-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)piperidin-4-yl)aceticacid

Powdered potassium hydroxide (44.5 mg, 0.79 mmol) was added in oneportion to Intermediate 33-1 (60 mg, 0.16 mmol) in tert-butanol (5 mL).The resulting pale yellow suspension was stirred at 40° C. for 30minutes. The reaction mixture was quenched with acetic acid (0.073 mL,1.27 mmol) in EtOH (10.0 mL) and the resulting solution stirred for afurther 10 minutes before being evaporated to dryness. The resultingsolid was partitioned between water (20 mL) and EtOAc (20 mL). Theaqueous layer showed a pH=6. The organic layer was separated and theaqueous re-extracted with EtOAc (2×25 mL). The combined organics werewashed with brine (15 mL), dried over MgSO₄ and evaporated in vacuo togive crude product. This was recrystallised from hot EtOH (6 mL) to givea yellow solid which was washed with ethylacetate (5 mL) and dried undervacuum at room temperature to give the title compound (41.0 mg, 70.2%)as a yellow solid.

¹H NMR (400 MHz, DMSO) δ 1.28 (2H, m), 1.76 (2H, m), 1.86 (1H, m), 2.15(2H, d), 2.60 (3H, s), 2.71 (3H, s), 2.76 (2H, d), 3.79 (2H, d), 7.00(2H, d), 7.55 (1H, s), 7.60 (2H, d), 7.96 (1H, s); m/z 369 (M+H)⁺.

Intermediate 33-1 ethyl2-(1-(4-(6-cyano-3,5-dimethylpyrazin-2-yl)phenyl)piperidin-4-ylacetate

Pyridine (0.050 mL, 0.62 mmol) was added dropwise to Intermediate 33-2(78 mg, 0.31 mmol), ethyl 2-(piperidin-4-yl)acetate (79 mg, 0.46 mmol)and Copper(II) acetate (56.0 mg, 0.31 mmol) in anhydrous DCM (10 mL) Theresulting blue solution was stirred at 25° C. for 16 hours. The reactionmixture was diluted with DCM (25 mL), and washed with a 20% aqueous EDTAsolution (25 mL). The organic layer was evaporated to afford crudeproduct. The crude product was purified by flash silica chromatography,elution gradient 0 to 70% EtOAc in isohexane. Pure fractions wereevaporated to dryness to afford the title compound (53.0 mg, 45.4%) as apale yellow solid.

¹H NMR (400 MHz, DMSO) δ 1.20 (5H, m), 1.69 (2H, d), 1.84 (1H, m), 2.22(2H, m), 2.61 (6H, s), 2.71 (2H, m), 3.77 (2H, d), 4.02 (2H, m), 6.97(2H, m), 7.47 (2H, m); m/z 379 (M+H)⁺.

Intermediate 33-2 4-(6-Cyano-3,5-dimethylpyrazin-2-yl)phenylboronic acid

Sodium periodate (5.02 g, 23.45 mmol) was added in one portion toIntermediate 33-3 (2.62 g, 7.82 mmol) in THF (80 mL) and water (20 mL)and the cloudy suspension was stirred at room temperature for 30minutes. 1M HCl (5.47 mL, 5.47 mmol) was added and the reaction mixturewas stirred at room temperature for 2 hours. The THF was evaporatedunder reduced pressure, the reaction mixture was diluted with water (100mL) and extracted with ethyl acetate (2×100 mL). The combined extractswere washed with water (2×30 mL) and brine (30 mL), dried over sodiumsulfate, concentrated to dryness by rotary evaporation to give the titlecompound (1.980 g, 100%).

¹H NMR (400 MHz, DMSO) δ 2.62 (3H, s), 2.70 (3H, s), 7.60 (2H, d), 7.92(2H, d), 8.16 (2H, s); m/z 254 (M+H)⁺.

Intermediate 33-33,5-Dimethyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile

This compound was synthesised from Intermediate 33-4 using similarconditions as described in Intermediate 25-2 to give the title compound(70.0 mg, 50.4%) as a white crystalline solid.

¹H NMR (400 MHz, DMSO) δ 1.39 (12H, s), 2.68 (3H, s), 2.77 (3H, s), 7.73(2H, d), 7.88 (2H, d); HPLC tR=2.85 min.

Intermediate 33-4 4-(6-Cyano-3,5-dimethylpyrazin-2-yl)phenyltrifluoromethanesulfonate

Trifluoromethanesulphonic anhydride (27.3 mL, 166.57 mmol) was added toa stirred solution of Intermediate 33-5 (10.13 g, 41.64 mmol) in DCM(400 mL) cooled to 0° C., over a period of 20 minutes under nitrogen.The resulting slurry was then allowed to warm to ambient temperatureovernight under a nitrogen atmosphere. Triethylamine (46.4 mL, 333.14mmol) was added dropwise over 10 minutes (under ice bath cooling,keeping temperature between 5-10° C.) and the resulting solution stirredat 30° C. for 3 hours under nitrogen. The reaction mixture was dilutedwith DCM (200 mL), and washed sequentially with water (200 mL),saturated NaHCO₃ (200 mL), and saturated brine (100 mL). The organiclayer was dried over MgSO₄, filtered and evaporated to afford crudeproduct. The crude product was purified by flash silica chromatography,elution gradient 0 to 40% EtOAc in isohexane. Pure fractions wereevaporated to dryness to the title compound (9.87 g, 66.3%) as a yellowoil.

¹H NMR (400 MHz, DMSO) δ 2.68 (3H, s), 2.78 (3H, s), 7.74 (2H, d), 7.93(2H, d); m/z=mass ion not seen; HPLC tR=2.84 min.

Intermediate 33-5 6-(4-Hydroxyphenyl)-3,5-dimethylpyrazine-2-carboxamide

This compound was synthesised from Intermediate 21-4 and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (CAS 269409-70-3)using similar conditions as described in Intermediate 25-1 to give thetitle compound (10.13 g, 97%) as an orange solid.

¹H NMR (400 MHz, DMSO) δ 2.58 (3H, s), 2.71 (3H, s), 6.87 (2H, d),7.56-7.60 (3H, m), 7.95 (1H, s), 9.73 (1H, s); m/z 244 (M+H)⁺.

The following examples were synthesised using similar conditions asdescribed in Example 33 to give the desired compounds 34-39.

¹H NMR (400 MHz, m/z Example Structure DMSO) δ (M + H)⁺ 34

1.58 (2H, m), 1.72 (1H, m), 1.92 (1H, m), 2.53 (1H, m), 2.60 (3H, s),2.72 (3H, s), 2.90 (1H, m), 3.04 (1H, m), 3.58 (1H, m), 3.76 (1H, m),7.02 (2H, d), 7.56 (1H, s), 7.62 (2H, d), 7.96 (1H, s) 355 35

1.66 (2H, m), 1.80 (1H, m), 2.00 (1H, m), 2.61 (1H, m), 2.67 (3H, s),2.78 (3H, s), 2.98 (1H, t), 3.14 (1H, t), 3.65 (1H, d), 3.83 (1H, d),7.10 (2H, d), 7.63 (1H, s), 7.69 (2H, d), 8.02 (1H, s) 355 36

2.60 (3H, s), 2.71 (7H, m), 3.20 (2H, s), 3.27 (4H, m), 7.03 (2H, d),7.56 (1H, s), 7.63 (2H, d), 7.96 (1H, s) 370 37

1.20 (1H, m), 1.55 (1H, m), 1.69 (1H, m), 1.81 (1H, m), 1.98 (1H, m),2.17 (1H, m), 2.28 (1H, m), 2.60 (4H, m), 2.71 (3H, s), 2.81 (1H, t),3.73 (2H, t), 7.00 (2H, d), 7.56 (1H, s), 7.61 (2H, d), 7.96 (1H, s),12.11 (1H, s) 369 38

1.64 (2H, m), 1.90 (2H, m), 2.45 (1H, m), 2.60 (3H, s), 2.71 (3H, s),2.87 (2H, t), 3.76 (2H, d), 7.03 (2H, d), 7.56 (1H, s), 7.61 (2H, d),7.96 (1H, s), 12.19 (1H, s) 355 39

1.12 (3H, d), 1.39 (2H, m), 1.75 (3H, m), 2.27 (1H, m), 2.66 (3H, s),2.77 (5H, m), 3.91 (2H, m), 7.08 (2H, d), 7.62 (1H, s), 7.67 (2H, d),8.02 (1H, s), 12.14 (1H, s) 383

Example 402-(1-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)pyrrolidin-3-yl)aceticacid

Powdered potassium hydroxide (122 mg, 2.17 mmol) was added in oneportion to Intermediate 40-1 (170 mg, 0.43 mmol) in tert-butanol (5 mL).The resulting yellow suspension was stirred at 40° C. for 90 minutes.The reaction mixture was quenched with acetic acid (0.198 mL, 3.47 mmol)in EtOH (10.0 mL) and the resulting solution stirred for a further 10minutes before being evaporated to dryness. The resulting solid waspartitioned between water (20 mL) and EtOAc (20 mL). The aqueous layershowed a pH=6. The organic layer was separated and evaporated to drynessto afford crude product (185 mg). The crude product was dissolved in DCM(5.00 mL) and TFA (1.0 mL, 12.99 mmol) was added. The brown solution wasstirred at room temperature for 2 hours. The reaction mixture waspurified by ion exchange chromatography, using an SCX column. The columnwas eluted with DCM (100 mL) followed by MeOH (100 mL) and then thedesired product was eluted from the column using 0.35M NH₃/MeOH (100 mL)and fractions containing the product were evaporated to dryness toafford crude product as a yellow solid (110 mg). This product waspurified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μsilica, 50 mm diameter, 150 mm length), using decreasingly polarmixtures of water (containing 0.1% formic acid) and MeOH as eluents.Fractions containing the desired compound were evaporated to dryness toafford the title compound (76 mg, 49.5%) as a yellow solid.

¹H NMR (400 MHz, DMSO) δ 1.65 (1H, m), 2.13 (1H, m), 2.38 (2H, m), 2.55(4H, m), 2.65 (3H, s), 2.93 (1H, t), 3.26 (1H, m), 3.33 (1H, m), 3.47(1H, m), 6.55 (2H, d), 7.50 (1H, s), 7.56 (2H, d), 7.89 (1H, s), 12.13(1H, s); m/z 355 (M+H)⁺.

Example 41(1R,5S,6r)-3-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid

Powdered potassium hydroxide (101 mg, 1.79 mmol) was added in oneportion to Intermediate 41-1 (175 mg, 0.45 mmol) in tert-butanol (4 mL)at 40° C. under nitrogen. The resulting suspension was stirred at 40° C.for 6 hours. A thick precipitate formed so the reaction was quenchedwith acetic acid (0.205 mL, 3.59 mmol) in EtOH (10 mL) and the resultingsolution stirred for a further 10 minutes before being evaporated todryness. The crude material was treated with a 5% HCl in methanolsolution (10 mL), and stirred overnight. The mixture was then treatedwith powdered potassium hydroxide (101 mg, 1.79 mmol) in tert-butanol.The resulting mixture was stirred at 40° C. for 2 hours, before beingquenched with acetic acid (0.205 mL, 3.59 mmol) in EtOH (5 mL) andevaporated to a gum. The crude product was purified by preparative HPLC(Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mmlength), using decreasingly polar mixtures of water (containing 0.1%formic acid) and MeCN as eluents. Fractions containing the desiredcompound were evaporated to dryness to afford the title compound (66.5mg, 42.1%) as a yellow solid.

¹H NMR (400 MHz, DMSO) δ 1.51 (1H, t), 2.23-2.26 (2H, m), 2.66 (3H, s),2.77 (3H, s), 3.39 (2H, d), 3.72 (2H, d), 6.71 (2H, d), 7.62 (1H, s),7.66 (2H, d), 8.01 (1H, s,) COOH not seen; m/z 353 (M+H)⁺.

The following compounds were synthesised from Intermediate 33-2 and theappropriate amine using similar conditions as described in Intermediate33-1 to give the desired Intermediates 34-1 to 40-1.

¹H NMR (400 MHz, m/z Intermediate Structure DMSO) δ (M + H)⁺ 34-1

1.27 (3H, t), 1.71 (3H, m), 1.99 (1H, m), 2.70 (7H, m), 3.04 (1H, m),3.23 (1H, m), 3.64 (1H, d), 3.83 (1H, d), 4.16 (2H, q), 7.10 (2H, d),7.61 (2H, d). 365 35-1

1.14 (3H, t), 1.59 (3H, m), 1.87 (1H, m), 2.58 (7H, m), 2.92 (1H, t),3.10 (1H, t), 3.52 (1H, d), 3.71 (1H, d), 4.04 (2H, q), 6.98 (2H, d),7.49 (2H, d). 365 36-1

2.60 (3H, s), 2.71 (7H, m), 3.20 (2H, s), 3.27 (4H, m), 7.03 (2H, d),7.56 (1H, s), 7.63 (2H, d), 7.96 (1H, s). 370 37-1

1.23 (1H, m), 1.55 (1H, m), 1.69 (1H, m), 1.79 (1H, m), 2.00 (1H, m),2.28 (1H, m), 2.38 (1H, m), 2.63 (7H, m), 2.83 (1H, m), 3.62 (3H, s),3.74 (2H, m), 7.01 (2H, d), 7.53 (2H, d). 365 38-1

1.13 (3H, t), 1.60 (2H, m), 1.86 (2H, m), 2.51 (1H, m), 2.59 (3H, s),2.61 (3H, s), 2.84 (2H, t), 3.72 (2H, d), 4.03 (2H, q), 6.98 (2H, d),7.48 (2H, d). 365 39-1^(a)

1.07 (3H, d), 1.18 (3H, t), 1.31 (2H, m), 1.68 (3H, m), 2.30 (1H, m),2.65 (3H, s), 2.66 (3H, s), 2.73 (2H, m), 3.87 (2H, t), 4.07 (2H, m),7.02 (2H, d), 7.52 (2H, d). 393 40-1

1.39 (1H, m), 1.42 (9H, s), 1.69 (1H, m), 2.16 (1H, m), 2.40 (2H, m),2.59 (1H, m), 2.65 (6H, s), 2.96 (1H, t), 3.37 (1H, m), 3.50 (1H, m),6.61 (2H, d), 7.53 (2H, d). 393 41-1^(a)

1.41 (9H, s), 1.42-1.45 (1H, m), 2.17-2.19 (2H, m), 2.64 (3H, s), 2.65(3H, s), 3.27 (2H, d), 3.66 (2H, d), 6.64 (2H, d), 7.51 (2H, d). 391Note: 39-1^(a) ethyl 2-(piperidin-4-yl)propanoate, CAS 141060-27-7 wasprepared according to the procedure described in WO 2008042925. 41-1^(a)(1R,5S,6r)-tert-butyl 3-azabicyclo[3.1.0]hexane-6-carboxylate, CAS681424-89-5 (prepared according to the procedure described in WO2004033451).

Example 422-((1r,4s)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)-2-methylpropanoicacid

Powdered potassium hydroxide (193 mg, 3.44 mmol) was added in oneportion to Intermediate 42-1 (470 mg, 1.15 mmol) in tert-butanol (20 mL)at 40° C. under nitrogen. The resulting suspension was stirred at 40° C.for 2 hours. The reaction was incomplete so the temperature wasincreased to 100° C. and the reaction mixture was stirred for a further16 hours. The reaction was quenched with acetic acid (0.329 mL, 5.74mmol) in EtOH (10 mL) and the resulting solution stirred for a further20 minutes before being evaporated to dryness. The resulting solid waspartitioned between water (50 mL) and EtOAc (50 mL). The aqueous layerwas acidified with 2M HCl (5 mL) was added and the organic layer wasseparated and the aqueous re-extracted with EtOAc (50 mL). The combinedorganics were washed with saturated brine (50 mL) and evaporated invacuo to give crude solid product. This was recrystallised from hot EtOH(15 mL) and washed with ether (10 mL) and dried under vacuum at roomtemperature to give the title compound (90 mg, 19.83%) as a pink solid.

¹H NMR (400.13 MHz, DMSO) δ 1.06 (6H, s), 1.15-1.30 (2H, m), 1.43-1.56(2H, m), 1.60-1.80 (3H, m), 1.80-1.95 (2H, m), 2.40-2.60 (1H, m), 2.58(3H, s), 2.73 (3H, s), 3.29 (3H, s), 7.36 (2H, d), 7.57 (1H, s), 7.64(2H, d), 7.97 (1H, s), 12.03 (1H, s); m/z 396 (M+H)⁺.

Intermediate 42-1 Methyl2-((1r,4r)-4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)-2-methylpropanoate

This compound was synthesised from Intermediate 42-2 and Intermediate21-4 using similar conditions as described in Intermediate 25-1 to givethe title compound (494 mg, 44.8%).

¹H NMR (400 MHz, CDCl₁) δ 1.10 (6H, s), 1.12-1.28 (2H, m), 1.40-1.53(2H, m), 1.60-1.73 (3H, m), 1.90-2.00 (2H, m), 2.43-2.52 (1H, m), 2.60(3H, s), 2.91 (3H, s), 3.62 (3H, s), 5.42 (1H, s), 7.25 (2H, d), 7.44(2H, dt), 7.72 (1H, s); m/z 410 (M+H)⁺.

Intermediate 42-2 Methyl2-methyl-2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)propanoate

To a solution of diisopropylamine (4.83 mL, 34.17 mmol) in THF (50 mL)under nitrogen, cooled to −70° C. was added butyllithium (21.35 mL,34.17 mmol) dropwise while maintaining the temperature between −70 and−60° C. After 30 minutes Intermediate 42-3 (3.18 g, 8.54 mmol) in THF(20 mL) was added and the mixture was allowed to warm to ˜20° C. over 90minutes. The solution was cooled to −65° C., methyl iodide (2.129 mL,34.17 mmol) was added and the reaction allowed to stir for 1 hour andthen allowed to warm to −30° C. The reaction was quenched with saturatedammonium chloride (100 mL), extracted with EtOAc (200 mL), the organicphase separated, washed with water (100 mL) and saturated brine (100mL). The organic layer was dried over MgSO₄, filtered and evaporated toafford crude product (2.99 g). The crude product was purified by flashsilica chromatography, elution gradient 0 to 10% EtOAc in isohexane.Pure fractions were evaporated to dryness to afford the title compound(1.830 g, 55.5%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.15 (6H, s), 1.15-1.28 (2H, m), 1.33 (12H,s), 1.49 (2H, dd), 1.65-1.75 (3H, m), 1.90-1.98 (2H, m), 2.42-2.51 (1H,m), 3.68 (3H, d), 7.21 (2H, d), 7.74 (2H, dd); m/z (EI+) 386 M⁺.

Intermediate 42-3 Methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)propanoate

Lithium bis(trimethylsilyl)amide (16.75 mL, 16.75 mmol) was added tomethyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate(CAS 701232-69-1) (prepared according to the procedure described in WO2004047755) (5 g, 13.96 mmol) in THF (50 mL) at 0° C. under nitrogen.The resulting solution was stirred at 0° C. for 30 minutes and thenmethyl iodide (1.304 mL, 20.93 mmol) was added and the reaction stirredfor 30 minutes. The reaction was quenched with saturated ammoniumchloride (50 mL), extracted with EtOAc (100 mL), the organic phaseseparated, washed with water (50 mL) and saturated brine (50 mL). Theorganic layer was dried over MgSO₄, filtered and evaporated to affordcrude product. The crude product was purified by flash silicachromatography, elution gradient 0 to 10% EtOAc in isohexane. Purefractions were evaporated to dryness to afford the title compound (3.38g, 65.1%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.08-1.30 (5H, m), 1.33 (12H, s), 1.40-1.70(3H, m), 1.70-1.97 (4H, m), 2.31 (1H, t), 2.43-2.53 (1H, m), 3.68 (3H,m), 7.21 (2H, d), 7.74 (2H, d); m/z 395 (M+Na)⁺.

Example 432-((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl)cyclohexyl)aceticacid

This compound was synthesised from Intermediate 43-1 using similarconditions as described in Example 21. Except the crude product waspurified by crystallisation from boiling EtOH (6 mL) to afford the titlecompound (89 mg, 43.6%).

¹H NMR (400 MHz, DMSO) δ 1.09-1.22 (3H, m), 1.53-1.61 (2H, m), 1.72-1.89(4H, m), 2.14-2.16 (2H, m), 2.60 (3H, s), 2.73 (3H, s), 2.79-2.87 (1H,m), 7.43-7.48 (1H, m), 7.53 (1H, d), 7.56-7.60 (2H, m), 8.04 (1H, s),12.11 (1H, s); m/z 386 (M+H)⁺.

Intermediate 43-1 Ethyl2-((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl)cyclohexyl)acetate

This compound was synthesised from Intermediate 43-2 and Intermediate21-4 using similar conditions as described in Intermediate 21-1 to givethe title compound (0.219 g, 23.90%) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.21 (3H, t), 1.54-1.64 (2H, m), 1.87-1.98(7H, m), 2.26 (2H, d), 2.67 (3H, s), 2.86-2.94 (1H, m), 2.98 (3H, s),4.13-4.18 (2H, m), 5.91 (1H, s), 7.24-7.36 (3H, m), 7.78 (1H, s); m/z414 (M+H)⁺.

Intermediate 43-2 Ethyl2-((1r,4r)-4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate

This compound was synthesised from Intermediate 43-3 using similarconditions as described in Intermediate 25-2 to give the title compound(0.865 g, 43.8%) as a white crystalline solid.

¹H NMR (400 MHz, CDCl₃) δ 1.09-1.17 (2H, m), 1.21 (3H, t), 1.26 (2H, s),1.46 (12H, s), 1.48-1.54 (2H, m), 1.78-1.87 (4H, m), 2.73-2.81 (1H, m),3.42 (1H, d), 4.05-4.11 (2H, m), 7.11 (1H, d), 7.14 (1H, d), 7.19-7.21(1H, m).

Intermediate 43-3 Ethyl2-((1r,4r)-4-(2-fluoro-4-(trifluoromethylsulfonyloxy)-phenyl)cyclohexyl)acetate

This compound was synthesised from Intermediate 43-4 using similarconditions as described in Intermediate 25-4 to give the title compound(2.087 g, 62.2%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.14-1.25 (2H, m), 1.27 (3H, t), 1.46-1.56(3H, m), 1.83-1.94 (4H, m), 2.24 (2H, d), 2.79-2.87 (1H, m), 4.12-4.17(2H, m), 6.96-6.99 (1H, m), 7.01-7.05 (1H, m), 7.27-7.31 (1H, m); m/z411 (M−H)⁻.

Intermediate 43-4 Ethyl2-((1r,4r)-4-(2-fluoro-4-hydroxyphenyl)-cyclohexyl)acetate andIntermediate 43-5 Ethyl2-(1s,4s)-4-(2-fluoro-4-hydroxyphenyl)-cyclohexyl)acetate

Intermediate 43-6 (6.29 g, 22.60 mmol) and palladium on carbon (10%)(0.6 g, 0.56 mmol) in EtOH (200 mL) was evacuated with hydrogen (4cycles) and then stirred under a balloon of hydrogen at ambienttemperature for 2 hours. The reaction mixture was filtered andevaporated to give a colourless oil. The crude product was purified byflash silica chromatography, elution gradient 10 to 20% EtOAc inisohexane. Pure fractions were evaporated to dryness to afford thedesired product as a mixture of cis and trans isomers as a colourlessoil which was further purified by preparative chiral-HPLC on a ChiralcelOJ column, eluting isocratically with 10% IPA in isohexane as eluent.The fractions containing the desired compounds were evaporated todryness to afford Intermediate 43-4 (2.28 g, 36%) as a white solid andIntermediate 43-5 (3.08 g, 48.6%) as a pale yellow gum.

Intermediate 43-4

¹H NMR (400 MHz, CDCl₃) δ 1.11-1.24 (2H, m), 1.26 (3H, t), 1.42-1.53(2H, m), 1.80-1.89 (5H, m), 2.23 (2H, d), 2.69-2.76 (1H, m), 4.14 (2H,q), 4.82 (1H, s), 6.50-6.57 (2H, m), 7.04 (1H, t); m/z (EI+) 280 M.

Intermediate 43-5

¹H NMR (400 MHz, CDCl₃) δ 1.27 (3H, t), 1.59-1.76 (8H, m), 2.29-2.36(1H, m), 2.45 (2H, d), 2.75-2.83 (1H, m), 4.15 (2H, q), 4.94 (1H, s),6.51-6.57 (2H, m), 7.08 (1H, t); m/z (EI+) 280 M⁺.

Intermediate 43-6 Ethyl2-(4-(2-fluoro-4-hydroxyphenyl)cyclohex-3-enyl)acetate

A solution of Intermediate 43-7 (18.48 g, 62.82 mmol) in DMF (100 mL)was added to a stirred suspension of 4-bromo-3-fluorophenol (10 g, 52.36mmol), potassium carbonate (21.71 g, 157.07 mmol) and[1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.163 g,1.41 mmol) in DMF (100 mL) at ambient temperature. The resultingsuspension was stirred at 80° C. under nitrogen for 2 hours. Thereaction was incomplete so the temperature was increased to 100° C. andthe reaction mixture was stirred for a further 30 minutes and thenfurther [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)(1.163 g, 1.41 mmol) was added and the suspension was stirred at 100° C.for a further 45 minutes and then further[1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (400 mg,0.487 mmol) was added and the suspension was stirred at 100° C. for afurther 45 minutes. The reaction mixture was evaporated to dryness andredissolved in EtOAc (200 mL) and 2M HCl (250 mL) was cautiously added.The aqueous layer was further extracted with EtOAc (3×200 mL) and theorganic extracts were combined, washed saturated brine (300 mL), driedover MgSO₄, filtered and evaporated to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness toafford the title compound (6.34 g, 43.5%) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.27 (3H, t), 1.41-1.50 (1H, m), 1.85-1.95(2H, m), 2.14-2.21 (1H, m), 2.32 (2H, d), 2.32-2.48 (3H, m), 4.16 (2H,q), 4.98 (1H, s), 5.81 (1H, s), 6.51-6.56 (2H, m), 7.05-7.09 (1H, m);m/z 277 (M−H)⁻.

Intermediate 43-7 Ethyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyl)acetate

This compound was synthesised from Intermediate 43-8 using similarconditions as described in Intermediate 25-2 to give the title compound(10.4 g, 71%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ1.24-1.28 (18H, m), 1.77-1.80 (2H, m),2.18-2.27 (2H, m), 2.20-2.24 (2H, m), 4.09-4.16 (2H, m), 6.51 (1H, d)

Intermediate 43-8 Ethyl2-(4-(trifluoromethylsulfonyloxy)cyclohex-3-enyl)acetate

Trifluoromethanesulfonic anhydride (11.9 mL, 70.86 mmol) was addedportionwise to a solution of 2,6-di-tert-butyl-4-methylpyridine (18.19g, 88.58 mmol) in DCM (250 mL). A solution of ethyl2-(4-oxocyclohexyl)acetate (10.88 g, 59.05 mmol, CAS 58012-34-3) in DCM(100 mL) was then added dropwise and the reaction mixture was allowed tostir open to air and at room temperature overnight. The reaction mixturewas washed with water, saturated Na₂CO₃, saturated brine, dried overMgSO₄ and evaporated to afford crude product. The crude product waspurified by flash silica chromatography, elution gradient 0 to 10% EtOAcin isohexane. Pure fractions were evaporated to dryness to afford thetitle compound (16.05 g, 86%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 1.22-1.29 (3H, m), 1.39-1.51 (1H, m),1.76-1.85 (2H, m), 2.07-2.23 (4H, m), 2.29 (2H, d), 4.09-4.18 (2H, m),4.96 (1H, s).

Example 442-((1s,4s)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl)cyclohexyl)aceticacid

This compound was synthesized from Intermediate 44-1 using similarconditions as described in Example 21 to give the title compound (252mg, 71%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 1.65 (8H, m), 2.22 (1H, m), 2.41 (2H, d), 2.60(3H, s), 2.74 (3H, s), 2.88 (1H, m), 7.53 (4H, m), 8.05 (1H, s), 12.03(1H, s); m/z 386 (M+H)⁺.

Intermediate 44-1 Ethyl2-((1s,4s)-4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl)cyclohexyl)acetate

This compound was synthesized from Intermediate 44-2 and Intermediate21-4 using similar conditions as described in Intermediate 21-1 to givethe title compound (453 mg, 68%) as a pale yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 1.28 (3H, t), 1.74 (8H, m), 2.39 (1H, m), 2.48(2H, d), 2.68 (3H, s), 2.97 (4H, m), 4.16 (2H, q), 5.51 (1H, s), 7.26(1H, m), 7.32 (1H, m), 7.38 (1H, t), 7.75 (1H, s); m/z 414 (M+H)¹.

Intermediate 44-2 Ethyl2-((1s,4s)-4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate

This compound was synthesized from Intermediate 44-3 using similarconditions as described in Intermediate 25-2 to give the title compound(1.45 g, 61%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.27 (3H, t), 1.32 (12H, s), 1.67 (8H, m),2.35 (1H, m), 2.46 (2H, d), 2.89 (1H, m), 4.14 (2H, q), 7.25 (1H, t),7.42 (1H, d), 7.52 (1H, d); m/z (ES+) (M+H)+=No mass ion; HPLC tR=3.62min.

Intermediate 44-3 Ethyl2-((1s,4s)-4-(2-fluoro-4-(trifluoromethylsulfonyloxy)-phenyl)cyclohexyl)acetate

This compound was synthesized from Intermediate 43-5 using similarconditions as described in Intermediate 25-4 to give the title compound(2.53 g, 86%) as a yellow oil.

¹H NMR (400 MHz, DMSO) δ 1.12 (3H, t), 1.55 (8H, m), 2.15 (1H, m), 2.41(2H, d), 2.77 (1H, m), 4.00 (3H, q), 7.24 (1H, m), 7.43 (1H, m), 7.56(1H, t); m/z (ES−) 411 (M−H)⁻.

Example 45((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenyl)cyclohexyl)aceticacid

This compound was synthesised from Intermediate 45-1 using similarconditions as described in Example 21. Except the crude product wasrecrystallised from hot EtOH (15 mL) to give a solid which was washedwith Ether (10 mL) and dried under vacuum at room temperature to givethe title compound (313 mg, 80%).

¹H NMR (400 MHz, DMSO) δ 1.12-1.23 (2H, m), 1.49-1.60 (2H, m), 1.76-1.90(5H, m), 2.18 (2H, d), 2.60 (3H, s), 2.75 (3H, s), 2.91-3.00 (1H, m),7.52 (1H, d), 7.65 (1H, s), 7.67-7.70 (1H, m), 7.84 (1H, d), 8.10 (1H,s), 12.09 (1H, s); m/z 402 (M+H)⁺.

Intermediate 45-1 Ethyl2-((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenyl)cyclohexyl)acetate

This compound was synthesized from Intermediate 45-2 and Intermediate21-4 using similar conditions as described in Intermediate 21-1 to givethe title compound (482 mg, 91%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 1.21 (3H, t), 1.40-1.47 (1H, m), 1.84-1.94(4H, m), 2.20 (2H, d), 2.60 (3H, s), 2.91 (3H, s), 2.94-3.02 (1H, m),3.42 (4H, d), 4.06-4.11 (2H, m), 5.40 (1H, s), 7.29-7.32 (1H, m),7.36-7.38 (1H, m), 7.51 (1H, d), 7.67 (1H, s); m/z 430 (M+H)⁺.

Intermediate 45-2 Ethyl2-((1r,4r)-4-(2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate

This compound was synthesized from Intermediate 45-3 using similarconditions as described in Intermediate 25-2 to give the title compound(1.046 g, 70.7%) as a colourless oil which crystallised on standing.

¹H NMR (400 MHz, CDCl₃) δ 0.76-0.87 (4H, m), 1.20 (3H, t), 1.35-1.44(1H, m), 1.48 (12H, s), 1.80-1.86 (4H, m), 2.18 (2H, d), 2.89-2.97 (1H,m), 4.05-4.10 (2H, m), 7.18 (1H, d), 7.56 (1H, d), 7.70 (1H, d); m/z 430(M+Na)⁺.

Intermediate 45-3 Ethyl2-((1r,4r)-4-(2-Chloro-4-(trifluoromethyl-sulfonyloxy)phenyl)cyclohexyl)acetate

This compound was synthesized from Intermediate 45-4 using similarconditions as described in Intermediate 25-4 to give the title compound(1.560 g, 85%) as a yellow oil.

¹H NMR (400 MHz, CDCl₁) δ 1.18-1.29 (4H, m), 1.39-1.49 (2H, m),1.88-1.95 (4H, m), 2.25 (2H, d), 2.93-3.01 (1H, m), 3.49 (2H, d),4.12-4.18 (2H, m), 7.14-7.17 (1H, m), 7.29 (1H, d), 7.32 (1H, d); m/z427 (M−H)⁻.

Intermediate 45-4 Ethyl2-((1r,4r)-4-(2-chloro-4-hydroxyphenyl)-cyclohexyl)acetate andIntermediate 45-5 Ethyl2-((1s,4s)-4-(2-chloro-4-hydroxyphenyl)cyclohexyl)acetate

These compounds were synthesized from Intermediate 45-6 using similarconditions as described in Intermediate 43-4 and 43-5, except aftersilica chromatography the crude product was purified by preparative HPLC(Phenomenex Gemini C18 110A (axia) column, 5μ, silica, 21 mm diameter,150 mm length), using decreasingly polar mixtures of water (containing0.1% formic acid) and MeCN as eluents. Fractions containing the desiredcompound were evaporated to dryness to afford crude product as a mixtureof isomers (5.78 g, 49.9%) as a colourless oil. The oil was purified bypreparative chiral-HPLC on a Merck 50 mm 20 μm Chiralcel OJ column,eluting isocratically with 70% isohexane in IPA (modified withAcOH/Et₃N) as eluent. The fractions containing the desired compound wereevaporated to dryness to afford Intermediate 45-4 (1.264 g, 21.87%) as awhite solid and Intermediate 45-5 (3.52 g, 60.9%) as white solid.

Intermediate 45-4

¹H NMR (400 MHz, CDCl₃) δ 1.13-1.24 (2H, m), 1.27 (3H, t), 1.34-1.45(2H, m), 1.80-1.91 (5H, m), 2.24 (2H, d), 2.84-2.92 (1H, m), 4.12-4.18(2H, m), 6.70-6.73 (1H, m), 6.86 (1H, d), 7.08 (1H, d) phenol OH notseen; m/z (ES−) (M−H)−=295, 297

Intermediate 45-5

¹H NMR (400 MHz, CDCl₃) δ 1.27 (3H, t), 1.46-1.58 (3H, m), 1.65-1.78(5H, m), 2.33-2.40 (1H, m), 2.47 (2H, d), 2.89-2.96 (1H, m), 4.13-4.18(2H, m), 6.70-6.73 (1H, m), 6.86 (1H, d), 7.12 (1H, d) phenol OH notseen; m/z (ES−) (M−H)−=295, 297

Intermediate 45-6 Ethyl2-(4-(2-chloro-4-hydroxyphenyl)cyclohex-3-enyl)acetate

This compound was synthesized from Intermediate 43-7 and4-bromo-3-chlorophenol using similar conditions as described inIntermediate 43-6 to give the title compound (5.30 g, 74.7%) as acolourless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.21 (3H, t), 1.36-1.45 (1H, m), 1.58 (1H, s),1.76-1.87 (2H, m), 2.07-2.17 (1H, m), 2.22-2.29 (4H, m), 4.07-4.12 (2H,m), 5.16 (1H, s), 5.50-5.52 (1H, m), 6.59-6.62 (1H, m), 6.78 (1H, d),6.93 (1H, d); m/z 293 (M−H)⁻.

Example 462-((1s,4s)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenyl)cyclohexyl)aceticacid

This compound was synthesized from Intermediate 46-1 using similarconditions as described in Example 21 to give the title compound (184mg, 44%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 1.65 (8H, m), 2.24 (1H, m), 2.44 (2H, d), 2.59(3H, s), 2.73 (3H, s), 2.99 (1H, m), 7.58 (2H, m), 7.67 (1H, d), 7.81(1H, s), 8.05 (1H, s), 12.01 (1H, s); m/z 402 (M+H)⁺.

Intermediate 46-1 Ethyl2-((1s,4s)-4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenyl)cyclohexyl)acetate

This compound was synthesized from Intermediate 46-2 and Intermediate21-4 using similar conditions as described in Intermediate 21-1 to givethe title compound (365 mg, 78%) as a colourless gum.

¹H NMR (400 MHz, CDCl₃) δ 1.28 (3H, t), 1.67 (2H, m), 1.78 (6H, m), 2.42(1H, m), 2.50 (2H, d), 2.67 (3H, s), 2.98 (3H, s), 3.10 (1H, m), 4.16(2H, m), 5.53 (1H, s), 7.43 (2H, m), 7.59 (1H, d), 7.75 (1H, s); m/z 430(M+H)⁺.

Intermediate 46-2 Ethyl2-((1s,4s)-4-(2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate

This compound was synthesized from Intermediate 46-3 using similarconditions as described in Intermediate 25-2 to give the title compound(1.19 g, 62%) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.27 (3H, t), 1.33 (12H, s), 1.59 (2H, m),1.72 (6H, m), 2.39 (1H, m), 2.47 (2H, d), 3.05 (1H, m), 4.15 (2H, q),7.28 (1H, t), 7.64 (1H, d), 7.77 (1H, s); m/z 430 (M+Na)⁺.

Intermediate 46-3 Ethyl2-((1s,4s)-4-(2-chloro-4-(trifluoromethyl-sulfonyloxy)phenyl)cyclohexyl)acetate

This compound was synthesized from Intermediate 45-5 using similarconditions as described in Intermediate 25-4 to give the title compound(2.051 g, 71.0%) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.26 (3H, t), 1.56 (2H, m), 1.73 (6H, m), 2.40(1H, m), 2.46 (2H, d), 3.02 (1H, t), 4.16 (1H, q), 7.16 (1H, m), 7.30(1H, d), 7.37 (1H, d); m/z 427 (M−H)⁻.

Example 476-(4-((1r,4r)-4-((1H-Tetrazol-5-yl)methyl)cyclohexyl)phenyl)-3,5-dimethylpyrazine-2-carboxamide

This compound was synthesised from Intermediate 47-1 using similarconditions as described in Example 28 to give the title compound (220mg, 41.7%) as a white solid. The material was recrystallised from hotMethanol, filtered off and washed with ether before drying under vacuumto give the title compound (223 mg, 42.3%).

¹H NMR (300 MHz, DMSO) δ 1.13-1.27 (2H, m), 1.43-1.56 (2H, m), 1.74-1.88(5H, m), 2.53-2.57 (1H, m), 2.58 (3H, s), 2.74 (3H, s), 2.84 (2H, d),7.35 (2H, d), 7.58 (1H, s), 7.65 (2H, d), 7.97 (1H, s), 16.00 (1H, s);m/z 392 (M+H)⁺.

Intermediate 47-13-(5-(((1r,4r)-4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)methyl)-1H-tetrazol-1-yl)propanenitrile

This compound was synthesised from Intermediate 47-2 using similarconditions as described in Intermediate 28-1 to give the title compound(1.960 g, 59.9%) contaminated with triphenyphosphine oxide (3 mol %).

¹H NMR (400 MHz, DMSO) δ 0.96-1.05 (2H, m), 1.06 (12H, s), 1.19-1.30(2H, m), 1.54-1.64 (5H, m), 2.67 (2H, d), 2.97 (2H, t), 3.07 (1H, s),4.47 (2H, t), 7.02 (2H, d), 7.37 (2H, d); HPLC tR=2.81.

Intermediate 47-2N-(2-Cyanoethyl)-2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetamide

This compound was synthesised from Intermediate 47-3 using similarconditions as described in Intermediate 28-2 to give the title compound(3.08 g, 77%).

¹H NMR (400 MHz, DMSO) δ 1.03-1.13 (2H, m), 1.27 (12H, s), 1.37-1.47(2H, m), 1.71-1.80 (5H, m), 2.02 (2H, d), 2.63 (2H, t), 7.22 (2H, d),7.58 (2H, d), 8.16 (1H, t), 3×CH obscured by solvent.

Intermediate 47-32-((1r,4r)-4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)aceticacid

Methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate(CAS 701232-69-1, prepared according to the procedure described in WO2004/047755) (3.6 g, 10.05 mmol) was dissolved in a solution of sodiumhydroxide (1.326 g, 33.16 mmol) in methanol (36 mL) and water (4.00 mL).The reaction mixture was split in two and heated to 120° C. for 30 minin a microwave. The reaction mixtures were combined, acidified with 2MHCl and evaporated. The crude product was taken onto the next stepwithout purification.

¹H NMR (400 MHz, DMSO) δ 1.08-1.12 (2H, m), 1.27 (12H, s), 1.42-1.46(2H, m), 1.74-1.82 (5H, m), 2.13 (2H, d), 7.22 (2H, d), 7.58 (2H, d) oneCH and COOH not seen.

Example 484′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)biphenyl-4-carboxylic acid

This compound was synthesised from Intermediate 48-1 using similarconditions as described in Example 21 to give the title compound (42.2mg, 74.5%) as an off white solid.

¹H NMR (400 MHz, DMSO) δ 2.58 (3H, s), 2.70 (3H, s), 3.57 (2H, s), 7.32(2H, d), 7.55 (1H, s), 7.64 (2H, d), 7.73 (2H, d), 7.78 (2H, d), 7.96(1H, s), 12.29 (1H, s); m/z 362 (M+H)⁺.

Intermediate 48-1 Methyl4′-(6-cyano-3,5-dimethylpyrazin-2-yl)biphenyl-4-carboxylate

This compound was synthesised from Intermediate 33-3 and methyl4-bromobenzoate using similar conditions as described in Intermediate21-1 to give the title compound (124 mg, 72.1%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 2.68 (3H, s), 2.72 (3H, s), 3.89 (3H, s), 7.80(2H, d), 7.89-7.93 (4H, m), 8.07 (2H, d); HPLC tR=2.92 min.

The following examples were synthesised from Intermediates 49-1- to 53-1using similar conditions as described in Example 21 to give the desiredcompounds.

¹H NMR (400 MHz, m/z Example Structure DMSO) δ (M + H)⁺ 49

2.64 (3H, s), 2.76 (3H, s), 3.63 (2H, s), 7.38 (2H, d), 7.61 (1H, s),7.70 (2H, d), 7.79 (2H, d), 7.84 (2H, d), 8.02 (1H, s), 12.33 (1H, s).362 50

2.55 (2H, t), 2.64 (3H, s), 2.75 (3H, s), 2.87 (2H, t), 7.35 (2H, d),7.61 (1H, s), 7.65 (2H, d), 7.77 (2H, d), 7.83 (2H, d), 8.02 (1H, s).COOH not seen. 376 51

2.65 (3H, s), 2.76 (3H, s), 7.35 (1H, t), 7.61 (2H, d), 7.77 (2H, d),7.82-7.86 (3H, m), 8.05 (1H, s), 8.19 (1H, s), COOH not seen. 348 52

2.71 (3H, s), 2.82 (3H, s), 3.74 (2H, s), 7.36 (1H, d), 7.51 (1H, t),7.69 (3H, d), 7.85 (2H, d), 7.92 (2H, d), 8.09 (1H, s), 12.43 (1H, s).362 53

2.61 (2H, t), 2.64 (3H, s), 2.76 (3H, s), 2.92 (2H, t), 7.26 (1H, d),7.40 (1H, t), 7.56 (1H, d), 7.60-7.63 (2H, m), 7.79 (2H, d), 7.84 (2H,d), 8.02 (1H, s), 12.12 (1H, s). 376

The following Intermediates were synthesised from Intermediate 33-3 andthe appropriate aryl bromide or triflate using similar conditions asdescribed in Intermediate 21-1 to give the desired compounds.

¹H NMR (400 MHz, m/z Intermediate Structure DMSO) δ (M + H)⁺ 49-1^(a)

2.75 (3H, s), 2.79 (3H, s), 3.70 (3H, s), 3.81 (2H, s), 7.46 (2H, d),7.78 (2H, d), 7.82 (2H, d), 7.89 (2H, d) HPLC tR = 2.83 min 50-1^(b)

2.73-2.77 (5H, m), 2.78 (3H, s), 2.98 (2H, t), 3.35 (3H, s), 7.42 (2H,d), 7.74 (2H, d), 7.81 (2H, d), 7.87 (2H, d) HPLC tR = 2.97 min.51-1^(c)

2.75 (3H, s), 2.79 (3H, s), 3.97 (3H, s), 7.74 (1H, t), 7.86 (2H, d),7.95 (2H, d), 8.05-8.08 (1H, m), 8.10- 8.13 (1H, m), 8.34 (1H, t). HPLCtR = 2.93 min. 52-1^(d)

2.75 (3H, s), 2.79 (3H, s), 3.70 (3H, s), 3.85 (2H, s), 7.38 (1H, d),7.52 (1H, t), 7.70-7.73 (2H, m), 7.83 (2H, d), 7.88 (2H, d). 35853-1^(e)

2.74 (3H, s), 2.76-2.80 (5H, m), 3.02 (2H, t), 3.66 (3H, s), 7.34 (1H,d), 7.48 (1H, t), 7.64 (1H, d), 7.68- 7.69 (1H, m), 7.82 (2H, d), 7.89(2H, d). 372 Note: 49-1^(a) methyl 2-(4-bromophenyl)acctatc, CAS41841-16-1 was made according to the procedure described by E. E. Knausat al, Bioorg. Med. Chem., 2005, 13, 4694-4703. 50-1^(b) methyl3-(4-(trifluoromethylsulfonyloxy)phenyl)propanoate, CAS 475272-11-8. wasmade according to the procedure described in WO 2002089738. 51-1^(c)methyl 3-bromobenzoate, CAS 618-89-3. 52-1^(d) methyl2-(3-bromophenyl)acetate, CAS 150529-73-0. 53-1^(e) methyl3-(3-bromophenyl)propanoate, CAS 151583-29-8 was made according to theprocedure described in WO 2007089667.

The following Examples 54-56 were synthesised from Intermediates 54-1 to56-1 using similar conditions as described in Example 26 and Examples 57to 63 were synthesised from Intermediates 57-1 to 63-1 using similarconditions as described in Example 21. All crude products were purifiedby preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50mm diameter, 150 mm length), using decreasingly polar mixtures of water(containing 0.1% formic acid) and MeCN as eluents. Fractions containingthe desired compound were evaporated to dryness to afford the desiredproducts.

¹H NMR m/z Example Structure DMSO) δ (M + H)⁺ 54

2.45 (3H, s), 2.75 (3H, s), 3.62 (2H, s), 7.38 (2H, d), 7.60 (1H, s),7.66-7.68 (3H, m), 7.73 (2H, d), 7.96 (1H, s), 12.33 (1H, s) 380 55

2.40 (3H, s), 2.78 (3H, s), 3.64 (2H, s), 7.39 (2H, d), 7.60-7.62 (2H,m), 7.73 (2H, d), 7.78-7.81 (1H, m), 7.90 (1H, d), 7.92 (1H, s), 12.35(1H, s) 396 56

2.41 (3H, s), 2.87 (3H, s), 3.72 (2H, s), 7.49 (2H, d), 7.65 (1H, s),7.75 (1H, d), 7.84 (3H, d), 8.17 (2H, t), COOH not seen. 430 57

2.65 (3H, s), 2.76 (3H, s), 3.60 (2H, s), 3.83 (3H, s), 7.31 (2H, d),7.34-7.43 (3H, m), 7.47 (2H, d), 7.60 (1H, s), 8.05 (1H, s). COOH notseen. 392 58

2.37 (3H, s), 2.75 (3H, s), 3.63 (2H, s), 3.87 (3H, s), 7.35-7.40 (4H,m), 7.45 (1H, d), 7.55 (1H, s), 7.72 (2H, d), 7.91 (1H, s), 12.34 (1H,s). 392 59

2.75 (3H, s), 2.84 (3H, s), 3.72 (2H, s), 7.48 (2H, d), 7.53 (2H, d),7.70 (1H, s), 7.74-7.80 (2H, m), 8.20 (1H, s), 12.47 (1H, s) 398 60

2.59 (3H, s), 2.71 (3H, s), 3.59 (2H, s), 7.32-7.34 (2H, m), 7.39-7.41(2H, m), 7.48 (1H, d), 7.57 (1H, s), 7.73-7.75 (1H, m), 7.92 (1H, d),8.04 (1H, s), 12.31 (1H, s). 396 61

2.68 (3H, s), 2.78 (3H, s), 3.66 (2H, s), 7.42 (2H, d), 7.59 (2H, dd),7.64 (1H, m), 7.69 (2H, dd), 7.80 (1H, dd), 8.10 (1H, s), 12.40 (1H, s).380 62

2.15 (3H, s), 2.37 (3H, s), 2.77 (3H, s), 3.62 (2H, s), 7.37 (3H, m),7.54 (1H, s), 7.58 (1H, d), 7.67 (3H, m), 7.90 (1H, s), 12.34 (1H, s).376 63

2.04 (6H, s), 2.63 (3H, s), 2.75 (3H, s), 3.63 (2H, s), 7.14 (2H, d),7.37 (2H, d), 7.47 (2H, s), 7.60 (1H, s), 8.00 (1H, s), 12.33 (1H, s).390

The following Intermediates 54-1 to 63-1 were synthesised fromIntermediates 54-2 to 63-2 and Intermediate 21-4 using similarconditions as described in Intermediate 21-1 to afford the desiredcompounds.

¹H NMR (400 MHz, m/z Intermediate Structure DMSO) δ (M + H)⁺ 54-1

1.48 (9H, s), 2.53 (3H, s), 2.83 (3H, s), 3.69 (2H, s), 7.45 (2H, d),7.69 (1H, s), 7.74-7.78 (3H, m), 7.82 (2H, d), 8.05 (1H, s) 436 55-1

1.42 (9H, s), 2.40 (3H, s), 2.78 (3H, s), 3.63 (2H, s), 7.38 (2H, d),7.59-7.62 (2H, m), 7.74 (2H, d), 7.78- 7.81 (1H, m), 7.90-7.91 (2H, m)452 56-1

1.42 (9H, s), 2.34 (3H, s), 2.80 (3H, s), 3.64 (2H, s), 7.41 (2H, d),7.59 (1H, s), 7.68 (1H, d), 7.75 (1H, s), 7.79 (2H, d), 8.09-8.11 (2H,m) 486 57-1

2.65 (3H, s), 2.77 (3H, s), 3.64 (3H, s), 3.72 (2H, s), 3.84 (3H, s),7.31 (2H, d), 7.36-7.42 (3H, m), 7.49 (2H, d), 7.61 (1H, s), 8.05 (1H,s) 406 58-1

2.37 (3H, s), 2.75 (3H, s), 3.64 (3H, s), 3.75 (2H, s), 3.87 (3H, s),7.36-7.40 (4H, m), 7.45 (1H, d), 7.55 (1H, s), 7.73 (2H, d), 7.90 (1H,s) 406 59-1

2.75 (3H, s), 2.84 (3H, s), 3.72 (3H, s), 3.84 (2H, s), 7.49 (2H, d),7.55 (2H, d), 7.71 (1H, s), 7.75-7.80 (2H, m), 8.20 (1H, s). 412 60-1

2.71 (3H, s), 2.83 (3H, s), 3.72 (3H, s), 3.95 (2H, s), 7.46 (2H, d),7.52-7.54 (2H, m), 7.60 (1H, d), 7.69 (1H, s), 7.85-7.87 (1H, m), 8.05(1H, d), 8.16 (1H, s). 410 61-1

(CDCl₃) δ 2.65 (3H, s), 2.93 (3H, s), 3.63 (2H, s), 3.66 (3H, s), 5.58(1H, s), 7.31-7.39 (4H, m), 7.46- 7.53 (3H, m), 7.69 (1H, s). 394 62-1

2.16 (3H, s), 2.36 (3H, s), 2.78 (3H, s), 3.64 (3H, s), 3.74 (2H, s),7.38 (3H, d), 7.55 (1H, s), 7.59 (1H, d), 7.67 (3H, m), 7.90 (1H, s).390 63-1

2.05 (6H, s), 2.63 (3H, s), 2.75 (3H, s), 3.66 (3H, s), 3.76 (2H, s),7.15 (2H, d), 7.38 (2H, d), 7.47 (2H, s), 7.60 (1H, s), 8.00 (1H, s).404

The following Intermediates 54-2 to 63-2 were synthesised fromIntermediates 54-3 to 63-3 using similar conditions as described inIntermediate 25-2 to afford the desired compounds.

Intermediate Structure ¹H NMR (400 MHz) m/z 54-2

(CDCl₃) δ 1.38 (12H, s), 1.45 (9H, s), 3.56 (2H, s), 7.24-7.27 (1H, m),7.33- 7.38 (3H, m), 7.55 (2H, d), 7.77-7.80 (1H, m) 412 M^(+.) (EI+)55-2

(CDCl₃) δ 1.39 (12H, s), 1.45 (9H, s), 3.56 (2H, s), 7.34 (2H, d),7.43-7.45 (1H, m), 7.53 (2H, d), 7.58 (1H, s), 7.75 (1H, d) 428 M^(+.)(EI+) 56-2

(CDCl₃) δ 1.38 (12H, s), 1.46 (9H, s), 3.57 (2H, s), 7.37 (2H, d), 7.56(2H, d), 7.72 (1H, d), 7.80 (1H, d), 7.87 (1H, s) 462 M^(+.) (EI+) 57-2

(CDCl₃) δ 1.36 (12H, s), 3.65 (2H, s), 3.71 (3H, s), 3.85 (3H, s),7.31-7.33 (3H, m), 7.39 (1H, s), 7.47- 7.51 (3H, m) 382 M^(+.) (EI+)58-2

(DMSO) δ 1.34 (12H, s), 3.35 (3H, s), 3.80 (2H, s), 3.89 (3H, s), 7.24(1H, d), 7.26-7.28 (1H, m), 7.43 (2H, d), 7.67 (1H, d), 7.72 (2H, d)mass ion not seen; HPLC tR = 3.01 min. 59-2

(DMSO) δ 1.38 (12H, s), 3.70 (3H, s), 3.82 (2H, s), 7.40 (2H, d), 7.46(4H, s) mass ion not seen; HPLC tR = 3.30 min. 60-2

(DMSO) δ 1.31 (12H, s), 3.64 (3H, s), 3.75 (2H, s), 7.35-7.41 (4H, m),7.42 (1H, d), 7.65-7.67 (1H, m), 7.72 (1H, d). mass ion not seen; HPLCtR = 3.42 min. 61-2

(DMSO) δ 1.31 (12H, s), 3.63 (3H, s), 3.74 (2H, s), 7.36-7.46 (3H, m),7.52 (2H, dd), 7.55 (2H, d). 388 M + Na⁺ 62-2

(DMSO) δ 1.30 (12H, s), 2.52 (3H, s), 3.62 (3H, s), 3.72 (2H, s), 7.26(1H, m), 7.40 (3H, m), 7.62 (2H, d), 7.70 (1H, d). no mass ion seen HPLCtR = 3.44 min 63-2

(DMSO) δ 1.28 (12H, s), 1.94 (6H, s), 3.64 (3H, s), 3.74 (2H, s), 7.06(2H, d), 7.34 (2H, d), 7.41 (2H, s). no mass ion seen HPLC tR = 3.39min.

The following Intermediates 54-3 to 63-3 were synthesised fromIntermediates 54-4 to 63-4 either using similar conditions as describedin Intermediate 25-4 (Method A) or by Method B (the procedure describedby A. Bengtson, A. Hallberg and M. Larhed, Org. Lett., 2002, 4,1231-1233) to afford the desired compounds.

Representative Example of Method B Intermediate 54-3 tert-Butyl2-(3′-fluoro-4′-(trifluoromethylsulfonyl-oxy)biphenyl-4-yl)acetate

Intermediate 54-4 (637 mg, 2.11 mmol),1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(753 mg, 2.11 mmol) and potassium carbonate (874 mg, 6.32 mmol) weresuspended in THF (11 mL) and sealed into a microwave tube. The reactionwas heated to 120° C. for 6 minutes in the microwave reactor and cooledto RT. The suspension was filtered, the solid was washed with EtOAc (20mL) and the filtrate was evaporated to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness toafford the title compound (690 mg, 75%) as a colourless oil.

m/z Intermediate Structure ¹H NMR (400 MHz) (M − H)⁻ 54-3

(CDCl₃) δ 1.46 (9H, s), 3.58 (2H, s), 7.35-7.39 (4H, m), 7.43-7.51 (3H,m) 433 55-3

(CDCl₃) δ 1.46 (9H, s), 3.57 (2H, s), 7.36-7.41 (3H, m), 7.48-7.53 (3H,m), 7.71 (1H, s) 449 56-3

(CDCl₃) δ 1.46 (9H, s), 3.59 (2H, s), 7.40 (2H, d), 7.52 (2H, d), 7.56(1H, d), 7.80-7.83 (1H, m), 7.92 (1H, d) 483 57-3

(CDCl₃) δ 3.67 (2H, s), 3.72 (3H, s), 3.83 (3H, s), 6.85 (1H, d),6.92-6.95 (1H, m), 7.33-7.35 (3H, m), 7.44 (2H, d) 404 58-3

(DMSO) δ 3.63 (3H, s), 3.74 (2H, s), 3.99 (3H, s), 7.30-7.33 (1H, m),7.38 (2H, d), 7.48 (1H, d), 7.52 (1H, d), 7.69 (2H, d) 403 59-3

(DMSO) δ 3.70 (3H, s), 3.83 (2H, s), 7.46-7.52 (4H, m), 7.74 (2H, d).409 60-3

(DMSO) δ 3.71 (3H, s), 3.82 (2H, s), 7.43-7.50 (4H, m), 7.64-7.69 (2H,m), 7.95 (1H, d). mass ion not seen; HPLC tR = 3.14 min. 61-3

(DMSO) δ 3.63 (3H, s), 3.75 (2H, s), 7.41 (2H, dd), 7.53 (2H, dt), 7.72(1H, d), 7.73 (1H, t). 391 62-3

(DMSO) δ 2.40 (3H, s), 3.63 (3H, s), 3.73 (2H, s), 7.27 (1H, m), 7.40(3H, m), 7.65 (2H, m), 7.77 (1H, s). 387 63-3

(DMSO) δ 2.01 (6H, s), 3.64 (3H, s), 3.73 (2H, s), 7.12 (2H, d), 7.26(2H, s), 7.37 (2H, d). 401 Notes: Method A 58-3, 59-3, 60-3; Method B54-3, 55-3, 56-3, 57-3, 61-3, 62-3, 63-3

The following Intermediates 54-4 to 63-4 were synthesised from eitherIntermediate 54-5 or 54-7 and the appropriate bromophenol using similarconditions as described in Intermediate 21-1 to afford the desiredcompounds.

m/z Intermediate Structure ¹H NMR (400 MHz) (M − H)⁻ 54-4^(a)

(CDCl₃) δ 1.45 (9H, s), 3.55 (2H, s), 5.11 (1H, d), 7.04 (1H, t),7.24-7.27 (1H, m), 7.28-7.33 (3H, m), 7.46 (2H, d). 301 55-4^(b)

(CDCl₃) δ 1.45 (9H, s), 3.55 (2H, s), 5.54 (1H, s), 7.07 (1H, d),7.31-7.33 (2H, m), 7.38-7.41 (1H, m), 7.45-7.47 (2H, m), 7.54 (1H, d).317 56-4^(c)

(CDCl₃) δ 1.45 (9H, s), 3.55 (2H, s), 5.11 (1H, d), 7.04 (1H, t),7.24-7.27 (1H, m), 7.28-7.33 (3H, m), 7.46 (2H, d) 351 57-4^(d)

(CDCl₃) δ 3.65 (2H, s), 3.71 (3H, s), 3.78 (3H, s), 4.88 (1H, s),6.45-6.47 (1H, m), 6.51 (1H, s), 7.15 (1H, d), 7.29 (2H, d), 7.44 (2H,d) 271 58-4^(e)

(DMSO) δ 3.69 (3H, s), 3.75 (2H, s), 3.91 (3H, s), 6.90 (1H, d),7.11-7.13 (1H, m), 7.23 (1H, d), 7.35 (2H, d), 7.61 (2H, d), 9.10 (1H,s). mass ion not seen; HPLC tR = 2.20 min. 59-4^(f)

(DMSO) δ 3.38 (3H, s), 3.47 (2H, s), 6.28-6.34 (2H, m), 7.05-7.10 (4H,m), 10.18 (1H, s). 277 60-4^(g)

(DMSO) δ 3.63 (3H, s), 3.71 (2H, s), 6.80-6.83 (1H, m), 6.92 (1H, d),7.20 (1H, d), 7.28-7.33 (4H, m), 9.93 (1H, s). 275 61-4^(h)

(DMSO) δ 3.62 (3H, s), 3.70 (2H, s), 6.65 (1H, dd), 6.70 (1H, dd), 7.30(1H, d), 7.32 (2H, dd), 7.41 (2H, dd), 9.96 (1H, s). 259 62-4^(i)

(DMSO) δ 2.18 (3H, s), 3.62 (3H, s), 3.67 (2H, s), 6.83 (1H, d), 7.27(3H, d), 7.36 (1H, s), 7.50 (2H, d), 9.35 (1H, s). no mass ion seen HPLCtR = 2.28 min. 63-4^(j)

(DMSO) δ 1.87 (6H, s), 3.64 (3H, s), 3.71 (2H, s), 6.50 (2H, s), 7.03(2H, d), 7.29 (2H, d), 9.12 (1H, s). no mass ion seen HPLC tR = 2.31min. Notes: 54-4^(a) 4-Bromo-2-fluorophenol and Intermediate 54-555-4^(b) 4-Bromo-2-chlorophenol and Intermediate 54-5. 56-4^(c)4-Bromo-2-(trifluoromethyl)benzenol and Intermediate 54-5. 57-4^(d)4-Bromo-3-methoxyphenol and Intermediate 54-5. 58-4^(e)4-Bromo-2-methoxyphenol and Intermediate 54-7. 59-4^(f)4-Bromo-3,5-Difluorophenol and Intermediate 54-7. 60-4^(g)4-Bromo-3-chlorophenol and Intermediate 54-7. 61-4^(h)4-Bromo-3-fluorophenol and Intermediate 54-7. 62-4^(i)4-Bromo-2-methylphenol and Intermediate 54-7. 63-4^(j)4-Bromo-3,5-dimethylphenol and Intermediate 54-7.

Intermediate 54-5 tert-Butyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

This compound was synthesised from Intermediate 54-6 using similarconditions as described in Intermediate 25-2 to give the title compound(8.37 g, 69.3%) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.34 (12H, s), 1.42 (9H, s), 3.53 (2H, s),7.27 (2H, d), 7.75 (2H, d); m/z (EI+) 318 M.

Intermediate 54-6 tert-Butyl 2-(4-bromophenyl)acetate CAS 33155-58-7

N,N-Dimethylformamide di-tert-butyl acetal (29.8 mL, 124.44 mmol) wasadded portionwise over 10 minutes to a stirred solution of4-bromophenylacetic acid (13.38 g, 62.22 mmol) in toluene (400 mL) at85° C. The resulting solution was stirred at 85° C. for 4 hours andallowed to cool to ambient temperature. The reaction mixture wasevaporated afford crude product which was purified by flash silicachromatography, elution gradient 0 to 20% EtOAc in isohexane. Purefractions were evaporated to dryness to afford the title compound (10.29g, 61.0%) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 3.46 (2H, s), 7.14 (2H, d), 7.44(2H, d); m/z (EI+) 270 M.

Intermediate 54-7 Methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (CAS454185-98-9)

This compound was synthesised from methyl 2-(4-bromophenyl)acetate (CAS41841-16-1 made according to the procedure described by E. E. Knaus atal, Bioorg. Med. Chem., 2005, 13, 4694-4703) using similar conditions asdescribed in Intermediate 25-2 to afford the title compound (2.140 g,100%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.34 (12H, s), 3.64 (2H, s), 3.68 (3H, s),7.28 (2H, d), 7.77 (2H, d); m/z (EI+) 276 M.

Example 642-((1r,4r)-4-(4-(6-Carbamoyl-5-methylpyrazin-2-yl)phenyl)cyclohexyl)aceticacid

This compound was synthesised from Intermediate 64-1 using similarconditions as described in Example 21 to afford the title compound (120mg, 64.3%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 1.10-1.18 (2H, m), 1.49-1.53 (2H, m), 1.84 (4H,d), 2.15 (2H, d), 2.31-2.33 (1H, m), 2.65-2.67 (1H, m), 2.75 (3H, s),7.38 (2H, d), 7.70 (1H, s), 8.14 (2H, d), 8.22 (1H, s), 9.18 (1H, s),11.97 (1H, s); m/z 395 (M+H)⁺.

Intermediate 64-1 Methyl2-((1r,4r)-4-(4-(6-Carbamoyl-5-methylpyrazin-2-yl)phenyl)cyclohexyl)acetate

This compound was synthesised from Intermediate 64-2 and methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate(CAS 701232-69-1: see also Intermediate 64-8) using similar conditionsas described in Intermediate 21-1 to afford the title compound (194 mg,83%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.15 (3H, m), 1.60 (2H, m) 1.87 (4H, s),2.20-2.22 (2H, m), 2.40-2.50 (1H, m) 2.94 (3H, s), 3.63 (3H, s), 5.5(1H, s), 7.29 (2H, d), 7.80 (1H, s), 7.85 (2H, d), 8.95 (1H, s); m/z 368(M+H)⁺.

Intermediate 64-2 6-Chloro-3-methylpyrazine-2-carboxamide

This compound was synthesised from Intermediate 64-3 using similarconditions as described in Intermediate 21-4 to afford the titlecompound (109 mg, 83%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 2.89 (3H, s), 5.45-5.55 (1H, s), 7.45-7.55(1H, s), 8.56 (1H, s).

Intermediate 64-3 Methyl 6-chloro-3-methylpyrazine-2-carboxylate

A suspension of Intermediate 64-4 (314 mg, 1.87 mmol) and Phosphorusoxychloride (2.088 mL, 22.40 mmol) stirred at 90° C. for 70 minutes. Thereaction mixture was added dropwise to water (20 mL) over 2-3 hourswhile maintaining the temperature below 40° C. (external coolingrequired). The mixture was extracted with DCM (5×50 mL), the organiclayer was dried over MgSO₄, filtered and evaporated to afford a yellowoil. This was then purified by flash silica chromatography, elutiongradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated todryness to afford the title compound (142 mg, 40.8%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 2.76 (3H, s), 3.94 (3H, s), 8.56 (1H, s); m/z187 (M+H)⁺.

Intermediate 64-4 Methyl 6-hydroxy-3-methylpyrazine-2-carboxylate

A solution of Intermediate 64-5 (1.3 g, 5.79 mmol) in pyridine (58.5 mL)was stirred at 60° C. for 90 minutes. The reaction mixture wasevaporated to afford crude product. The crude product was purified byflash silica chromatography, elution gradient 50 to 80% EtOAc inisohexane. Pure fractions were evaporated to dryness to afford the titlecompound (0.340 g, 34.9%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.59 (3H, s), 3.94 (3H, s), 8.27 (1H, s); m/z169 (M+H)⁺.

Intermediate 64-5 (S)-Methyl 2-(2-aminoacetamido)-3-oxobutanoatehydrochloric acid salt

A 4M solution of Hydrogen chloride (7.98 mL, 31.91 mmol) in dioxane wasadded to Intermediate 64-6 (2.3 g, 7.98 mmol). The resulting solutionwas stirred at ambient temperature for 4 hours. The reaction mixture wasevaporated to afford the title compound (1.790 g, 119%) as a creamsolid, which was used without further purification. m/z 189 (M+H)⁺.

Intermediate 64-6 (S)-Methyl2-(2-(tert-butoxycarbonylamino)acetamido)-3-oxobutanoate

A solution of Intermediate 64-7 (12.9 g, 44.43 mmol) in DCM (72 mL) wasadded to a stirred suspension of pyridinium chlorochromate (22.99 g,106.64 mmol) in DCM (43 mL) at 0° C., over a period of 15 minutes underair. The resulting mixture was stirred at ambient temperature for 24hours. The reaction mixture was evaporated to dryness and ether (400 mL)and water (300 mL) were added. The suspension was filtered throughcelite and the flask was rinsed with ether (4×300 mL) and water (3×200mL). The washings were filtered through celite and the organic layerswere combined, washed with saturated brine (200 mL), The aqueous phasewas re extracted with EtOAc (2×500 mL), the organic layers were combineddried over MgSO₄, filtered and evaporated to afford 5.5 g of crudeproduct. The crude product was purified by flash silica chromatography,elution gradient 50 to 80% EtOAc in isohexane. Pure fractions wereevaporated to dryness to afford the title compound (18.29%) as a yellowoil.

¹H NMR (400 MHz, CDCl₃) δ 1.39 (9H, d), 1.97-2.01 (3H, m), 2.31 (2H, s),3.68 (1H, t), 3.75 (3H, s), 3.76-3.82 (3H, m), 4.05 (2H, q), 5.19 (1H,d).

Intermediate 64-7 Methyl2-(2-(tert-butoxycarbonylamino)acetamido)-3-hydroxybutanoate

HATU (46.9 g, 123.30 mmol) was added to a stirred solution of2-(tert-butoxycarbonylamino)acetic acid (18 g, 102.75 mmol) DMA (230 mL)at ambient temperature. After 5 minutes a solution of (2S,3R)-methyl2-amino-3-hydroxybutanoate hydrochloride (17.43 g, 102.75 mmol) andDIPEA (71.8 mL, 411.00 mmol) in DMA (230 mL) was added and the resultingsolution was stirred at ambient temperature for 20 hours, The reactionmixture was diluted with EtOAc (300 mL), and washed with 1N citric acid(300 mL), salt was added to the aqueous layer which was re extractedwith EtOAc (4×400 mL). The organic extracts were combined, washed withsaturated NaHCO₃ (200 mL), dried over MgSO₄, filtered and evaporated toafford crude product. The crude product was purified by flash silicachromatography, elution gradient 50 to 100% EtOAc in isohexane. Purefractions were evaporated to dryness to afford the title compound (12.97g, 43.5%) as a yellow glass which formed a solid on standing.

¹H NMR (400 MHz, CDCl₃) δ 1.16 (3H, t), 1.38 (9H, d), 3.70 (3H, s),3.80-3.81 (2H, m), 4.25-4.28 (1H, m), 4.51-4.54 (1H, m), 5.36 (1H, s),6.96 (1H, d); m/z 291 (M+H)⁺.

Intermediate 64-8 Methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate

Trimethylphosphonoacetate (1.05X-1.06X) was added dropwise to asuspended solution of t-BuOK (0.70X-0.71X) in 2-MeTHF (10 vol) at 5-10°C. The resulting solution was stirred at 15-20° C. for 3.5-4.0 hours.The reaction mixture was cooled to 5-10° C. and DIPEA (0.81-0.82X) wasadded to the reaction at 10-15° C. 4-(4-Hydroxyphenyl)cyclohexanone(1.0X) was added in portions to the above reaction mixture at 10-15° C.and the resulting solution was stirred at 15-20° C. for 3-6 hours andthen sampled for HPLC analysis. NH4Cl-sol (5.0X-6.0X) was added to thereaction mixture at 0-15° C., and the reaction was quenched. The organiclayer was separated and the aqueous layer was extracted with 2-MeTHF(2.5X-3.0X). The two organic extracts were combined and washed withNaHSO₃ aq. and then NaCl-solution (2.5X-3.0X) twice. The organic layerwas concentrated to 2-3 vol and n-heptane was added to give a suspendedsolution, and the above mixture was concentrated to below 3% of 2-MeTHFresidue to give a suspended solution. The mixture was cooled to 0-5° C.,stirred for 1.0-2.0 h, filtered and the cake washed with n-heptane (2vol X2). Dry in vacuum at below 45° C. to give the desiredphenoxyacrylate product.

AcOH (0.05X) and Toluene (20 vol) were added to a pressure reactor, thenthe above phenoxyacrylate (1.0X) was added to the mixture. The reactorwas carefully inertised, then 10% Pd/C (0.15X) was added to the reactionmixture under nitrogen protection. The agitation was slowed down and thenitrogen-atmosphere was exchanged by hydrogen three times, andhydrogenation was performed at 1200 mbar at 25-28° C. The resultingsolution was stirred at 25-28° C. for 14-18 h. HPLC showed conversionof >98%. The reaction mixture was filtered, and the cake was washed withEtOH (1.5X×2), then the filtrate was concentrated in vacuo to 2-3 vol,n-heptane(10 vol) was added to precipitate, then concentrated untiltoluene residue <1.0%, cooled to 0-5° C., filtered, the cake was driedin vacuo to dryness. The crude product was dissolved in EtOH:H₂O=2:1(1.09X of crude product) by heating to reflux and stirred at thistemperature for ˜5 min, then cooled slowly to 20° C. over 3 h andstirred at 20° C. for 1 h, followed by cooling slowly to 0˜5° C. over 90min and stirred at 0˜5° C. for 1 h. After filtering the filter cake waswashed with cold EtOH:H₂O=2:1 (0.18X×2 of crude product, 0˜5° C.). Thefilter cake was dried in vacuo at 45-50° C. for 24 h to give the puretrans-ester product.

The above trans ester (1.0X) was dissolved in anhydrous CH₂Cl₂ (12 vol),NMM (0.57X, 1.4 eq) was added dropwise to the mixture under N₂. Theresulting solution was cooled to −10˜0° C. and stirred for 10 min, thenTf₂O (1.36X, 1.2 eq) was added dropwise at −10˜0° C. (N.B. CF₃SO₂Cl canbe appropriately used in place of triflic anhydride Tf₂O). The resultingsolution was stirred at −10˜0° C. for 30 min, warmed to 0˜10° C. andstirred for 30 min. (sampled for HPLC analysis, conversion was >98%).10% citric acid solution (10.0X) was added dropwise to the mixture. Themixture was stirred for 10 min, the organic layer was separated, washedwith 10% citric acid (10.0X) and brine (10.0X), dried with anhydrousMgSO₄ (0.5X) for 2 hrs, filtered and concentrated to remove CH₂Cl₂.Heptane (10X) was added and concentrated to remove the residual CH₂Cl₂(expectation<1.0%), then the suspension in heptane was concentrated to1.5˜2.0 vol, the mixture was cooled to 0˜5° C. and stirred for 30˜60 minat 0˜5° C. After filtering the cake was dried under vacuum at 30˜40° C.to give the desired triflate as a white solid. Pinacoldiboron ester(0.8X, 1.2 eq), TBAF (0.13X, 0.2 eq) and KOAc (0.38X, 1.5 eq) weredissolved in CH₃CN (5 vol), then PCy₃ (1.5% X, 0.02 eq) and PdCl₂ (0.47%X, 0.01 eq) were added. The mixture was degassed with nitrogen. Asolution of the triflate (1.0X, 1.0 eq) in CH₃CN (7 vol) was added tothe mixture at 20-25° C. Then the resulting solution was heated toreflux and stirred for 16 hrs (overnight—sampled for HPLC analysis,conversion was >98%). The mixture was filtered via a pad of 20 umcellulose, activated carbon (0.2X) was added to the filtrate and theresulting solution was heated to reflux for 2˜3 hrs. The mixture wascooled to 40˜50° C. and then filtered and the filtrate was concentratedto dryness. The residue solid was dissolved in EtOAc, and the EtOAcsolution was washed with water (10 vol), 1N HCl (10 vol) and brine (10vol). The organic layer was separated and concentrated to 1˜2 vol, thenheptane (5˜6 vol) was added to the solution and concentrated until EtOAcwas removed (EtOAc/Heptane=0-1%), heptane (5˜6 vol) was added to theresulting solution and heated to 50˜60° C. for 30 min. There were twolayers (a clear upper heptane layer and a yellowish bottom layer). Theheptane layer was separated, heptane (5˜6 vol) was added to theyellowish bottom layer and heated to 50˜60° C. for 30 min, and theheptane layer was separated again. The heptane layers were combined andfiltered via silica gel. The filtrate was concentrated to 1˜1.5 vol andthe precipitate was filtered and dried in vacuo to give the desiredboronate ester as a white solid.

Example 65 Methyltrans-4-{4-[6-(aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}-cyclohexanecarboxylate

Ethyl chloroformate (245 μl, 2.54 mmol) was added dropwise to a stirredsolution of6-{4-[trans-4-(methoxycarbonyl)cyclohexyl]phenyl}-5-methylpyrazine-2-carboxylicacid (Intermediate 65-1, 751 mg, 2.12 mmol) and N-methylmorpholine (350μl 3.18 mmol) in DCM (20 mL) at 0° C. Ammonia (5 mL of a 7M solution inMeOH) was added. The reaction mixture was allowed to warm up over 1 hthen was concentrated and the residue was purified by chromatographyeluting with 0-10% MeOH/DCM to give the title compound (226 mg, 30%) asa solid; ¹H NMR δ 9.00 (1H, s), 8.08 (1H, s), 7.74 (1H, s), 7.70 (2H,d), 7.40 (2H, d), 3.63 (3H, s), 2.70-2.55 (1H, m), 2.67 (3H, s),2.50-2.35 (1H, m), 2.10-1.98 (2H, m), 1.96-1.83 (2H, m), 1.65-1.43 (4H,m); MS 354.

Intermediate 65-16-{4-[trans-4-(Methoxycarbonyl)cyclohexyl]phenyl}-5-methylpyrazine-2-carboxylicacid

Diaminopropionic acid hydrochloride (496 mg, 3.52 mmol) was added to astirred solution of methyltrans-4-(4-pyruvoylphenyl)cyclohexanecarboxylate (Intermediate 65-2, 844mg, 2.93 mmol) and triethylamine (1.6 mL, 11.72 mmol) in MeOH (6 mL).After 48 h the reaction mixture was concentrated and the residue wastriturated with ether to give the title compound (751 mg, 72%) as asolid that was used without further purification; ¹H NMR δ 9.04 (1H, s),7.62 (2H, d), 7.40 (2H, d), 3.64 (3H, obs. s), 2.70-2.55 (1H, m), 2.66(3H, s), 2.50-2.36 (1H, m), 2.08-1.96 (2H, m), 1.95-1.85 (2H, m),1.65-1.45 (4H, m); MS 355.

Intermediate 65-2 Methyltrans-4-(4-pyruvoylphenyl)cyclohexanecarboxylate

1,1,1-tris(Acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (5.14 g,12.12 mmol) was added to a stirred solution of methyltrans-4-(4-lactoylphenyl)cyclohexanecarboxylate (Intermediate 65-3,1.758 g, 6.06 mmol) in DCM (25 mL). The mixture was stirred for 1 h,hexanes (50 mL) was added and the mixture was filtered through a pad ofdiatomaceous earth. Volatile material was removed by evaporation to givethe title compound (1.55 g, 88%) as a solid that was used withoutfurther purification; ¹H NMR δ 7.88 (2H, d), 7.45 (2H, d), 3.63 (3H, s),2.70-2.57 (1H, m), 2.50 (3H, s), 2.48-2.36 (1H, m), 2.08-1.94 (2H, m),1.90-1.80 (2H, m), 1.60-1.40 (4H, m); MS 311 (M+Na)⁺.

Intermediate 65-3 Methyl trans-4-(4-lactoylphenyl)cyclohexanecarboxylate

Sodium hydroxide (370 mg, 9.25 mmol) in water (2 mL) was added to astirred solution of methyltrans-4-[4-(2-bromopropanoyl)phenyl]cyclohexanecarboxylate (prepared asdescribed in Patent Application WO2004/047755) (3.264 g, 9.25 mmol) inDMF (10 mL). The mixture was stirred for 40 minutes then extracted withether (5×20 mL). The extracts were combined, dried and concentrated. Thecrude product was purified by flash column chromatography eluting with20-40% EtOAc/hexanes to give the title compound (1.76 g, 66%) as asolid; ¹H NMR δ 7.94 (2H, d), 7.39 (2H, d), 5.29 (1H, d), 5.08-4.98 (1H,m), 3.62 (3H, s), 2.68-2.54 (1H, m), 2.48-2.35 (1H, m), 2.08-1.94 (2H,m), 1.90-1.79 (2H, m), 1.60-1.40 (4H, m), 1.28 (3H, s); MS 313 (M+Na)⁺.

Example 66trans-4-{4-[6-(Aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}cyclo-hexanecarboxylicacid

Lithium hydroxide monohydrate (42 mg, 1.00 mmol) was added to a stirredsolution of methyltrans-4-{4-[6-(aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}-cyclohexanecarboxylate(Example 65, 71 mg, 0.20 mmol) in MeOH (2 mL), THF (1 mL) and water (0.5mL). After 16 h the reaction mixture was concentrated in vacuo andpurified by reverse phase HPLC (150 mm×21 mm Phenomenex Column packedwith Luna 10u C18 silica, eluting with 5-95% acetonitrile/water) to givethe title compound as a yellow solid (6 mg, 9%); ¹H NMR δ 9.01 (1H, s),8.08 (1H, s), 7.73 (1H, s), 7.70 (2H, d), 7.40 (2H, d), 2.70-2.50 (1H,m), 2.65 (3H, s), 2.37-2.25 (1H, m), 2.10-2.00 (2H, m), 1.95-1.85 (2H,m), 1.65-1.40 (4H, m); MS 340.

Examples 67 to 70

Other compounds which have been made by processes analogous to thosedescribed herein are2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2′-methylbiphenyl-4-yl)aceticacid;2-(4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)naphthalen-1-yl)phenyl)aceticacid;2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2′-cyanobiphenyl-4-yl)aceticacid and2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-3′,5′-difluorobiphenyl-4-yl)aceticacid.

Alternative Preparations Intermediate 1-4 Ethyl6-chloro-3,5-dimethylpyrazine-2-carboxylate

A suspension of Intermediate 1-5 (268 g, 1365.93 mmol) in phosphorusoxychloride (1273 mL, 13659.31 mmol) was heated at 90° C. under nitrogenfor 1 hour then cooled to ambient temperature. The reaction wascautiously added to water (6 L) with vigorous stirring keeping thetemperature between 17° C. and 20° C. The mixture was then extractedwith DCM (5×2.5 L), washed with water, saturated brine and dried overMgSO₄ and evaporated to afford crude product. The crude product waspurified by flash silica chromatography, elution gradient 0 to 25% EtOAcin isohexane. Pure fractions were evaporated to dryness to afford thetitle compound (227 g, 77%) as a yellow oil which solidified onstanding.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (3H, t), 2.68 (3H, s), 2.77 (3H, s), 4.46(2H, q); m/z 215 (M+H)⁺.

Intermediate 1-5 Ethyl 6-hydroxy-3,5-dimethylpyrazine-2-carboxylate

A solution of 2M Hydrochloric acid in 1,4-dioxane (1177 mL, 4709.97mmol) was added to Intermediate 1-6 (745 g, 2354.99 mmol) and stirred atroom temperature for 15 minutes then warmed to 40° C. for a further 40minutes. Pyridine (6500 mL) was then slowly added and then the reactionwas heated to 80° C. for 2 hours in the presence of air. The reactionwas then allowed to cool to ambient temperature and evaporated todryness to afford a viscous oil. This was suspended in DCM (2.5 L) andwashed water (1.5 L). The DCM was then dried over MgSO₄, filtered andconcentrated to afford an orange semi-solid, which was triturated with1:1 EtOAc/iso-hexane (250 mL) to afford ethyl6-hydroxy-3,5-dimethyl-1,4-dihydropyrazine-2-carboxylate (127 g, 27.1%)as a cream solid. The mother liqours were then purified by flash silicachromatography (gradient from 20% ethyl acetate/iso-hexane to 80% ethylacetate/iso-hexane). Fractions containing the desired product wereconcentrated and the residue was triturated with a small volume of 1:1EtOAc/iso-hexane to afford the title compound (9.00 g, 1.948%).

Manganese dioxide (150 g) was added to a suspension of ethyl6-hydroxy-3,5-dimethyl-4,5-dihydropyrazine-2-carboxylate (121 g, 610.44mmol) in DCM (1.8 L) at ambient temperature giving rise to a 2° C.exotherm. The reaction was stirred for 10 minutes then warmed to 35° C.for 1 hour. The reaction was incomplete so an additional 115 g ofManganese dioxide was added and the reaction stirred for 1 hour at 35°C. then stirred to cool to ambient temperature. The reaction wasfiltered through a short bed of silica and washed through with 2 L of1:1 EtOAc/iso-hexane and finally 2×2 L EtOAc. The fractions were thencombined and reduce in-vacuo to give an orange solid, which was slurriedin 300 mL of 1:1 EtOAc/iso-hexane, filtered and washed with iso-hexaneto afford the title compound (87 g, 72.6%) as an orange solid.

¹H NMR (400 MHz, DMSO) δ 1.31 (3H, t), 2.35 (3H, s), 2.50 (3H, s), 4.31(2H, q), 11.93 (1H, s); m/z 197 (M+H)⁺

Intermediate 1-6 can Also be Prepared by the Following ProcedureIntermediate 1-6 Ethyl2-(2-(tert-butoxycarbonylamino)propanamido)-3-oxobutanoate

A solution of 4-methylmorpholine (900 g) in THF (15 L) was added to2-(tert-butoxycarbonylamino)propanoic acid (1690 g, 8933.17 mmol). Themixture was cooled to −25° C. and isobutyl chloroformate (1.164 L,8933.17 mmol) was added. After 20 minutes the second equivalent of4-methylmorpholine (900 g) was added followed by ethyl2-amino-3-oxobutanoate Tosylate salt (see J-P. Genet et al, Eur. J. Org.Chem., 2004, 3017-3026) (2700 g, 8507.78 mmol) suspended in THF (2.5 L).The mixture was stirred at −25° C. for 30 minutes and then left to warmto ambient temperature overnight. The reaction was quenched with water(15 L), extracted with EtOAc (3×5 L) and the combined extracts washedwith 50% saturated brine (5 L). The organic layer was dried over MgSO₄,filtered and evaporated to afford crude product. The crude product waspurified by flash silica chromatography, elution gradient 50 to 80%EtOAc in isohexane. Pure fractions were evaporated to dryness to affordethyl 2-(2-(tert-butoxycarbonylamino)propanamido)-3-oxobutanoate (1850g, 68.7%).

Example 12-((1r,4r)-4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)aceticacid

Powdered potassium hydroxide (2.81 g, 50.10 mmol) was added in oneportion to Intermediate 1-8 (6.37 g, 16.70 mmol) in tert-butanol (150mL) at 40° C. under nitrogen. The resulting suspension was stirred at40° C. for 20 minutes. A thick precipitate formed so the reaction wasquenched with acetic acid (4.78 mL, 83.49 mmol) in ethanol (100.0 mL)and the resulting solution stirred for a further 20 minutes before beingevaporated to dryness. The resulting solid was partitioned between water(500 mL) and EtOAc (500 mL). The aqueous layer showed a pH=4˜5. Theorganic layer was separated and the aqueous re-extracted with EtOAc(2×250 mL). The combined organics were washed with brine (100 mL), driedover MgSO₄ and evaporated in vacuo to give crude product. This wasrecrystallised from hot ethanol (250 mL) to give a yellow solid whichwas washed with ether (100 mL) and dried under vacuum at roomtemperature to give the title compound (4.82 g, 79%).

[¹H NMR (400.132 MHz, DMSO) δ 1.09-1.19 (2H, m), 1.46-1.57 (2H, m),1.70-1.78 (1H, m), 1.81-1.87 (4H, m), 2.15 (2H, d), 2.58 (3H, s), 2.73(3H, s), 3.29 (1H, s), 7.36 (2H, d), 7.57 (1H, s), 7.64 (2H, d), 7.98(1H, s), 11.98 (1H, s)].

A melting point with an onset value of approximately 225° C. has beendetermined for{trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid.

Intermediate 1-8 methyl2-((1s,4s)-4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)acetate

A solution of 6-chloro-3,5-dimethylpyrazine-2-carboxamide (seeIntermediate 21-4) (3.15 g, 16.97 mmol), methyl2-((1s,4s)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate(see Intermediate 64-8) (6.08 g, 16.97 mmol) and tripotassium phosphate(4.32 g, 20.37 mmol) in DME (120 mL), ethanol (75 mL) and water (30.0mL) were degassed before addition of(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.698 g,0.85 mmol). The reaction mixture was heated to 80° C., under nitrogen,and left to stir overnight for 16 hrs. The reaction mixture was allowedto cool to room temperature and then evaporated. The crude product waspartitioned between water (250 mL) and EtOAc (250 mL). The catalyst wasfiltered off from the biphasic mixture. The organic phase was separatedand washed with brine (100 mL), dried (Na₂SO₄) and evaporated. The crudeproduct was purified by flash silica chromatography, elution gradient 5to 90% EtOAc in isohexane on 330 g silicyle column. Pure fractions wereevaporated to dryness to afford the title compound (6.47 g, 100%) as ayellow solid.

[¹H NMR (400.132 MHz, DMSO) δ 1.10-1.21 (2H, m), 1.46-1.56 (2H, m),1.73-1.86 (5H, m), 2.25 (2H, d), 2.58 (3H, s), 2.73 (3H, s), 3.28 (1H,s), 3.60 (3H, s), 7.35 (2H, d), 7.58 (1H, s), 7.64 (2H, d), 7.97 (1H,s); HPLC tR=2.53 min.]

1. A compound of formula (I), or a pharmaceutically-acceptable salt, orpro-drug thereof,

wherein Ring A is 2,6-pyrazindiyl, 3,5-pyridindiyl or 2,6-pyridindiyl,each optionally substituted on an available carbon atom by one or twosubstituents independently selected from linear (1-3C)alkyl,(2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino andcyano; X is ═O or ═S; Ring B is 1,4-phenylene or Ring B is a di-linked(excluding links via the same or adjacent atoms) ring selected frompyridindiyl, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl,thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl and pyrazoldiyl;each optionally substituted on an available carbon atom by one or twosubstituents independently selected from halo, amino, cyano,(1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-4C)alkoxy and(1-4C)alkoxy-(1-4C)alkyl; Y₁ is a direct bond between Ring B and Ring Cor Y₁ is —O—, —S— or —NRa— wherein Ra is hydrogen or (1-4C)alkyl; Y₂ is—(CH₂)_(r)— wherein r is 2 or 3, and Y₂ is linked at the same carbonatom as Y₁ in Ring C and Y₂ is linked at an adjacent carbon atom to Y₁in Ring B; n is 0 or n is 1 when Y₁ is a direct bond between Ring B andRing C and when Ring B is 1,4-phenylene and Ring C is (4-6C)cycloalkane,so that a 5- or 6-membered spino-ring system is formed and Ring C istri-linked; Ring C is a di-linked (excluding links via the same oradjacent atoms) ring or ring system chosen from (4-6C)cycloalkane,(7-10C)bicycloalkane and (8-12C)tricycloalkane each optionallysubstituted on an available carbon atom, including the ring carbon atombearing the Z-containing group, by one substituent selected fromhydroxy, (1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl; or RingC is a di-linked (excluding links via the same or adjacent atoms) ringselected from phenylene, pryidindiyl, piperidinediyl N-linked to Y₁,piperazinediyl, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl,thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl, pyrazoldiyl andazabicyclo[3.1.0]hexanediyl; each optionally substituted on an availablecarbon atom by up to four substituents independently selected fromfluoro, chloro, bromo, cyano, (1-4C)alkyl, (1-4C)alkoxy and(1-4C)alkoxy(1-4C)alkyl; L is a direct bond to Ring C, —O—, —S— or —NH—;p is 0 (when L is a direct bond), 1 or 2 and when p is 1 or 2 R^(AI) andR^(A2) are each independently hydrogen or (1-4C)alkyl or R^(A1) andR^(A2) are linked together to form a (3-6C)spiroalkyl ring; Z is carboxyor a mimic or bioisostere thereof, hydroxy or —CONRbRc wherein Rb and Rcare independently selected from hydrogen and (1-4C)alkyl, which(1-4C)alkyl group may be optionally substituted by carboxy or a mimic orbioisostere thereof; and wherein any carbon atom in a linear(1-3C)alkyl, (1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy containing groupdefined above may be optionally substituted by up to 3 fluoro atoms;with the proviso that the compound(4-(4-(6-carbamoyl-pyridin-2-yl)phenyl)cyclohexyl)acetic acid isexcluded.
 2. A compound of formula (I), or a pharmaceutically-acceptablesalt, or pro-drug thereof, as claimed in claim 1, wherein Ring A is2,6-pyrazindiyl, 3,5-pyridindiyl or 2,6-pyridindiyl, each optionallysubstituted on an available carbon atom by one or two substituentsindependently selected from linear (1-3C)alkyl, (2-3C)alkenyl,(2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino and cyano; X is ═O or═S; Ring B is 1,4-phenylene or Ring B is a di-linked (excluding linksvia the same or adjacent atoms) ring selected from pyridindiyl,furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl, thiazoldiyl,imidazoldiyl, isoxazoldiyl, isothiazoldiyl and pyrazoldiyl; eachoptionally substituted on an available carbon atom by one or twosubstituents independently selected from halo, amino, cyano,(1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-4C)alkoxy and(1-4C)alkoxy-(1-4C)alkyl; Y₁ is a direct bond between Ring B and Ring Cor Y₁ is —O—, —S— or —NRa— wherein Ra is hydrogen or (1-4C)alkyl; Y₂ is—(CH₂)_(r)— wherein r is 2 or 3, and Y₂ is linked at the same carbonatom as Y₁ in Ring C and Y₂ is linked at an adjacent carbon atom to Y₁in Ring B; n is 0 or n is 1 when Y₁ is a direct bond between Ring B andRing C and when Ring B is 1,4-phenylene and Ring C is (4-6C)cycloalkane,so that a 5- or 6-membered spiro-ring system is formed; Ring C is adi-linked (excluding links via the same or adjacent atoms) ring or ringsystem chosen from (4-6C)cycloalkane, (7-10C)bicycloalkane and(8-12C)tricycloalkane each optionally substituted on an available carbonatom, including the ring carbon atom bearing the Z-containing group, byone substituent selected from hydroxy, (1-4C)alkyl, (1-4C)alkoxy and(1-4C)alkoxy(1-4C)alkyl; or Ring C is a di-linked (excluding links viathe same or adjacent atoms) ring selected from phenylene, pryidindiyl,piperidinediyl N-linked to Y₁, furandiyl, thiophendiyl, pyrroldiyl,oxazoldiyl, thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl andpyrazoldiyl; each optionally substituted on an available carbon atom byup to four substituents independently selected from fluoro, chloro,bromo, cyano, (1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl; Lis a direct bond to Ring C, —O—, —S— or —NH—; p is 0, 1 or 2 and when pis 1 R^(A1) and R^(A2) are each independently hydrogen or (1-4C)alkyl orR^(A1) and R^(A2) are linked together to form a (3-6C)spiroalkyl ring; Zis carboxy or a mimic or bioisostere thereof, hydroxy or —CONRbRcwherein Rb and Rc are independently selected from hydrogen and(1-4C)alkyl, which (1-4C)alkyl group may be optionally substituted bycarboxy or a mimic or bioisostere thereof; and wherein any carbon atomin a linear (1-3C)alkyl, (1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxycontaining group defined above may be optionally substituted by up to 3fluoro atoms.
 3. A compound of formula (IA) as claimed in claim 1 or 2,or a pharmaceutically-acceptable salt, or pro-drug thereof,

wherein X, Ring A, Ring B, Y₁, p, R^(AI), R^(A2) and Z are as defined inclaim 1 or
 2. 4. A compound of formula (IB) as claimed in claim 1 or 2,or a pharmaceutically-acceptable salt, or pro-drug thereof,

wherein X, Ring A, Ring B, Y₁, p, R^(A1), R^(A2) and Z are as defined inclaim 1 or
 2. 5. A compound as claimed in any one of claims 1 to 4, or apharmaceutically-acceptable salt, or pro-drug thereof, wherein X is ═O;Ring A is 2,6-pyrazindiyl optionally substituted on an available carbonatom by one or two substituents independently selected from linear(1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl,amino and cyano; Ring B is 1,4-phenylene optionally substituted on anavailable carbon atom by one or two substituents independently selectedfrom halo, amino, cyano, (1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl,(1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl; Ring C is 1,4-cyclohexane; nis 0 and Y₁ is a direct bond or Y₁ is —O—; L is a direct bond; p is 1and R^(A1) and R^(A2) are each hydrogen; Z is carboxy, a tetrazolegroup, —C(O)NHS(O)₂Me, hydroxy or —CONRbRc wherein Rb and Rc areindependently selected from hydrogen and (1-4C)alkyl, which (1-4C)alkylgroup may be optionally substituted by carboxy; and wherein any carbonatom in a linear (1-3C)alkyl, (1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxycontaining group defined above may be optionally substituted by up to 3fluoro atoms.
 6. A compound as claimed in any one of claims 1 to 5, or apharmaceutically-acceptable salt, or pro-drug thereof, wherein Ring A is2,6-pyrazindiyl optionally substituted on an available carbon atom byone or two linear (1-3C)alkyl substituents.
 7. A compound as claimed inclaim 1 or 2 selected from{trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid;3,5-Dimethyl-6-[4-(trans-4-{2-[(methylsulfonyl)amino]-2-oxoethyl}cyclohexyl)-phenyl]pyrazine-2-carboxamide;6-{4-[trans-4-(2-Amino-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxamide;N-({trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}acetyl)-2-methylalanine;6-{4-[trans-4-(2-Hydroxyethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxamide;(trans-4-{4-[6-Carbamoyl-5-(difluoromethyl)-3-methylpyrazin-2-yl]phenyl}cyclohexyl)aceticacid;{trans-4-[4-(6-Carbamoyl-3-ethyl-5-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid;{trans-4-[4-(6-Carbamoyl-5-ethyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid and{trans-4-[4-(6-Carbamoyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}aceticacid;2-((1r,4s)-5′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-yl)aceticacid;(1r,4s)-5′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carboxylicacid;2-((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)-2-methylpropanoicacid2-(1-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)pyrrolidin-3-yl)aceticacid;(1R,5S,6r)-3-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid;6-(4-((1r,4r)-4-((1H-Tetrazol-5-yl)methyl)cyclohexyl)phenyl)-3,5-dimethylpyrazine-2-carboxamide;4′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)biphenyl-4-carboxylic acid;Methyltrans-4-{4-[6-(aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}-cyclohexanecarboxylate;trans-4-{4-[6-(Aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}cyclo-hexanecarboxylicacid; or a pharmaceutically-acceptable salt of any of these.
 8. Acompound as claimed in any one of claims 1 to 6 wherein a pro-drugthereof is an ester of a carboxy group selected from a (1-6C)alkylester, a (1-6C)alkoxymethyl ester, a (1-6C)alkanoyloxymethyl ester, aphthalidyl ester, a (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl ester, a1,3-dioxolan-2-ylmethyl ester, a (1-6C)alkoxycarbonyloxyethyl ester, anaminocarbonylmethyl ester and a mono- or di-N-((1-6C)alkyl) version ofan aminocarbonylmethyl ester.
 9. A compound as claimed in any one ofclaims 1 to 6 wherein a mimic or bioisostere of a carboxy group isselected from —SO₃H, —S(O)₂NHR¹³, S(O)₂NHC(O)R¹³, —CH₂S(O)₂R¹³,—C(O)NHS(O)₂R¹³, —C(O)NHOH, —C(O)NHCN, —CH(CF₃)OH, C(CF₃)₂OH, —P(O)(OH)₂and groups of sub-formula (ω-(i′) below

wherein where p in sub-formula (k) is 1 or 2, R²⁷ and R²⁸ areindependently selected from hydrogen, hydroxy, (1-6C)alkoxy, thiol,(1-6C)alkylthio, —C(O)R²⁹, —S(O)R³⁰, —SO₂R³¹, —NR³²R³³, —NHCN, halogenand trihalomethyl, where R²⁹, R³⁰ and R³¹ are —OR³⁴, (1-6C)alkyl,—NR³²R³³ or trihalomethyl, R³² and R³³ are independently selected fromhydrogen, (1-6C)alkyl, —SO₂R³⁴ and —COR³⁵, where R³⁵ is (1-6C)alkyl ortrihalomethyl, and R³⁴ is hydrogen, (1-6C)alkyl or trihalomethyl and R¹³is selected from hydrogen, (1-6C)alkyl, hydroxy, halo, amino, cyano,((1-3 C)alkyl)CONH—, carboxy, (1-6C)alkoxy, (1-6C)alkoxycarbonyl,carbamoyl, N-((1-6C)alkyl)carbamoyl, halo((1-6C)alkyl) (such astrifluoromethyl), (1-6C)alkylsulphonyl or (1-6C)alkylsulphinyl.
 10. Acompound according to any one of claims 1 to 9 or apharmaceutically-acceptable salt, or pro-drug thereof for use as amedicament.
 11. A compound, or a pharmaceutically-acceptable salt, orpro-drug thereof, for use as a medicament as claimed in claim 10 fortreating diabetes mellitus and/or obesity in a warm-blooded animal suchas a human being.
 12. The use of a compound according to any one ofclaims 1 to 9, or a pharmaceutically-acceptable salt, or pro-drugthereof, in the manufacture of a medicament for use in the production ofan inhibition of DGAT-1 activity in a warm-blooded animal such as ahuman being.
 13. The use of a compound of formula (I), or apharmaceutically-acceptable salt, or pro-drug thereof, as claimed inclaim 12, in the manufacture of a medicament for use in the treatment ofdiabetes mellitus and/or obesity in a warm-blooded animal such as ahuman being.
 14. A method of treating diabetes mellitus and/or obesityin a warm-blooded animal, such as a human being, in need of suchtreatment which comprises administering to said animal an effectiveamount of a compound according to any one of claims 1 to 9, or apharmaceutically-acceptable salt, or pro-drug thereof.
 15. Apharmaceutical composition which comprises a compound of formula (I) asclaimed in any one of claims 1 to 9, or a pharmaceutically-acceptablesalt, or pro-drug thereof, in association with apharmaceutically-acceptable excipient or carrier.